rs122453118

Variant names:

• chrX-153694424-C-G
• rs122453118
• NM_005629.4:c.1473C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-153694424-C-G
• chrX-153694424-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_Supporting PP4_Strong PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1472G>A variant is a missense variant predicted to cause a substitution of a cysteine for a tryptophan at amino acid position 491 (p.Cys491Trp). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID:17101918) (PP4_Strong). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts, measured with 25uM creatine (PMID:22281021) (PS3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.751 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 11704). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256015/MONDO:0010305/027

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: -0.298

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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	c.1473C>G	p.Cys491Trp	missense_variant	Exon 10 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1443C>G	p.Cys481Trp	missense_variant	Exon 10 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1128C>G	p.Cys376Trp	missense_variant	Exon 10 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1473C>G	p.Cys491Trp	missense_variant	Exon 10 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Mar 25, 2024

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4:c.1472G>A variant is a missense variant predicted to cause a substitution of a cysteine for a tryptophan at amino acid position 491 (p.Cys491Trp). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts, measured with 25uM creatine (PMID: 22281021) (PS3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.751 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 11704). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on March 25, 2024). -

Nov 14, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.83		Gain of catalytic residue at C491 (P = 0.0576);.;.;
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		-1.1
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs122453118; hg19: chrX-152959879;