Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000162.5(GCK):c.1317C>T (p.Ile439=)

CA454606568

515200 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 415eb198-9c77-492e-9e2a-3731e09e3cd4

HGVS expressions

NM_000162.5:c.1317C>T

NM_000162.5(GCK):c.1317C>T (p.Ile439=)

NC_000007.14:g.44145217G>A

CM000669.2:g.44145217G>A

NC_000007.13:g.44184816G>A

CM000669.1:g.44184816G>A

NC_000007.12:g.44151341G>A

NG_008847.1:g.49207C>T

NG_008847.2:g.57954C>T

ENST00000395796.8:c.*1315C>T

ENST00000616242.5:c.*437C>T

ENST00000683378.1:n.543C>T

ENST00000336642.9:c.351C>T

ENST00000345378.7:c.1320C>T

ENST00000403799.8:c.1317C>T

ENST00000671824.1:c.1380C>T

ENST00000672743.1:n.329C>T

ENST00000673284.1:c.1317C>T

ENST00000336642.8:c.369C>T

ENST00000345378.6:c.1320C>T

ENST00000395796.7:c.1314C>T

ENST00000403799.7:c.1317C>T

ENST00000437084.1:c.1266C>T

ENST00000459642.1:n.697C>T

ENST00000616242.4:c.1314C>T

NM_000162.3:c.1317C>T

NM_033507.1:c.1320C>T

NM_033508.1:c.1314C>T

NM_000162.4:c.1317C>T

NM_001354800.1:c.1317C>T

NM_001354801.1:c.306C>T

NM_001354802.1:c.177C>T

NM_001354803.1:c.351C>T

NM_033507.2:c.1320C>T

NM_033508.2:c.1314C>T

NM_033507.3:c.1320C>T

NM_033508.3:c.1314C>T

NM_001354803.2:c.351C>T

Likely Benign

PM2_Supporting BP7 BP4 BP2

PS4 PP4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1317C>T variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 439 (p.(Ile439=)) of NM_000162.5. This synonymous variant is not predicted to impact splicing (SpliceAI score of 0.00 for donor gain, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of 0.274, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID 515200). The MODY probability is unable to be calculated for this individual due to lack of clinical information (ClinVar ID 515200). This variant has been observed in in unknown phase with the variant c.128G>A p.Arg43His (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). In summary, c.1317C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3,0, approved 8/11/2023): PM2_Supporting, BP2, BP4, BP7.

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

BP7

This synonymous variant is not predicted to impact splicing (SpliceAI score of 0.00 for donor gain, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of 0.274, which is below the MDEP cutoff of 2.0) (BP4, BP7).

BP4

BP2

This variant has been observed in in unknown phase with the variant c.128G>A p.Arg43His (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2).

PS4

This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID 515200).

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID 515200).

Approved on: 2024-01-22

Published on: 2024-01-22

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