rs2872524

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1714G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 572 (p.Val572Met). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population minor allele frequency MAF) is 0.0000369 (33/894244 alleles, 12 hemizygotes) in the European (Non-Finnish) population. This MAF is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There are 14 hemizygotes in gnomAD v4.1.0. (12 in the European non-Finnish, one in the "other" and one in the S. Asian population) (BS2). The computational predictor REVEL gives a score of 0.689, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 449188). Due to the presence of 14 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549625/MONDO:0010305/027

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.000039 ( 0 hom. 14 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 3.25

Variant links:

Genes affected

SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1714G>A	p.Val572Met	missense_variant	Exon 12 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1684G>A	p.Val562Met	missense_variant	Exon 12 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1369G>A	p.Val457Met	missense_variant	Exon 12 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.1714G>A	p.Val572Met	missense_variant	Exon 12 of 13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 link	c.1369G>A	p.Val457Met	missense_variant	Exon 12 of 13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 link	n.2021G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000397

AC:

AN:

176255

Hom.:

AF XY:

0.0000481

AC XY:

AN XY:

62357

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000644

Gnomad NFE exome

AF:

0.0000772

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000393

AC:

AN:

1094605

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

360917

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.000125

Gnomad4 NFE exome

AF:

0.0000393

Gnomad4 OTH exome

AF:

0.0000653

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000907

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Benign:2

Mar 13, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4:c.1714G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 572 (p.Val572Met). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population minor allele frequency MAF) is 0.0000369 (33/894244 alleles, 12 hemizygotes) in the European (Non-Finnish) population. This MAF is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There are 14 hemizygotes in gnomAD v4.1.0. (12 in the European non-Finnish, one in the "other" and one in the S. Asian population) (BS2). The computational predictor REVEL gives a score of 0.689, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 449188). Due to the presence of 14 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) -

Jul 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Sep 07, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the SLC6A8 gene. The V572M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V572M variant is observed in 6/35470 (0.02%) alleles from individuals of European background, including 3 unrelated hemizygous individuals in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V572M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However. in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.40

MVP

0.92

MPC

0.61

ClinPred

0.40

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over