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]

Variant: NM_005629.4(SLC6A8):c.644+9G>A

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CA10549215

416004 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 5f6f0c48-ac17-4a5d-96aa-6922f7827308

Approved on: 2023-01-12

Published on: 2023-01-24

HGVS expressions

NM_005629.4:c.644+9G>A

NM_005629.4(SLC6A8):c.644+9G>A

NC_000023.11:g.153691562G>A

CM000685.2:g.153691562G>A

NC_000023.10:g.152957017G>A

CM000685.1:g.152957017G>A

NC_000023.9:g.152610211G>A

NG_012016.1:g.8266G>A

NG_012016.2:g.8266G>A

ENST00000253122.10:c.644+9G>A

ENST00000675713.1:n.398+9G>A

ENST00000253122.9:c.644+9G>A

ENST00000429147.1:n.93+9G>A

ENST00000430077.6:c.299+9G>A

ENST00000466243.1:n.436+9G>A

ENST00000467402.1:n.145+55G>A

NM_001142805.1:c.644+9G>A

NM_001142806.1:c.299+9G>A

NM_005629.3:c.644+9G>A

NM_001142805.2:c.644+9G>A

Likely Benign

BP7 BP4

BS1 PP4 PM2

Evidence Links 0

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.644+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 3. This variant was reported in a female patient with intellectual disability (LOVD, https://databases.lovd.nl/shared/genes/SLC6A8; individual #00185850) but details of biochemical testing or brain MRS are not available (PMID: 20717164). The computational splicing predictors SpliceAI and varSEAK suggest that the variant has no impact on splicing (BP4). This is also supported by the reported results of 5 different predictors (Netgene2, Fruitfly (i.e. NNSplice), Splice predictor, Genscan W, FSplice) (PMID 20717164). PhyloP100 way score for this intronic variant is 0.35, which is below the threshols of 2.0, indicating that this nucleotide is not highly conserved (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001061 in the African population. This allele frequency is between the ClinGen CCDS VCEP’s allele frequency thresholds for PM2 (<0.00002) and BS1 (>0.0002). Therefore, neither code is met. There is a ClinVar entry for this variant (Variation ID: 416004) In summary, this variant meets the criteria to be classified as likely benign for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications verion 1.1.0): BP4. BP7. This classification was approved by the ClinGen CCDS VCEP on Jan 12, 2023).

BP7

The PhyloP100 way score is 0.35, indicating that this nucleotide is not highly conserved (BP7).

BP4

The computational splicing predictors SpliceAI and varSEAK both suggest that the variant has no impact on splicing (BP4). This is also supported by the reported results of 5 different predictors (Netgene2, Fruitfly (i.e. NNSplice), Splice predictor, Genscan W, FSplice) (PMID 20717164).

BS1

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001061 in the African population, which is lower than the ClinGen CCDS VCEP's allele frequency cutoff for BS1 (>0.0002) and, therefore, BS1 is not met.

PP4

This variant was reported in a female patient with intellectual disability (LOVD, https://databases.lovd.nl/shared/genes/SLC6A8; individual #00185850) but details of biochemical testing or brain MRS are not available (PMID: 20717164).

PM2

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001061 in the African population, which is higher than the ClinGen CCDS VCEP's allele frequency cutoff for PM2 (<0.00002) and, therefore, PM2 is not met. There are no hemizygotes in any population.

Curation History

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