NM_005629.4:c.283G>A

Variant names:

• chrX-153690395-G-A
• rs782040427
• NM_005629.4:c.283G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.283G>A variant in SLC6A8 is a missense variant predicted to cause a substitution of a valine by an isoleucine at amino acid position 95 (p.Val95Ile). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00005 (4/78678 alleles, 2 hemizygotes) in the European (Non-Finnish) population, which 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. The computational predictor REVEL gives a score of 0.644, 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: 449185, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; two submitters: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549177/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000017 (0 hom. 8 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: -2.22
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• creatine transporter deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.283G>A	p.Val95Ile	missense	Exon 2 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.283G>A	p.Val95Ile	missense	Exon 2 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.-63G>A		5_prime_UTR	Exon 2 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.283G>A	p.Val95Ile	missense	Exon 2 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.283G>A	p.Val95Ile	missense	Exon 2 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.283G>A	p.Val95Ile	missense	Exon 2 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.0000354 AC: 4 AN: 112846 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000189 AC: 3 AN: 158720 AF XY: 0.0000201

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000175 AC: 19 AN: 1086592 Hom.: 0 Cov.: 30 AF XY: 0.0000225 AC XY: 8 AN XY: 355054

African (AFR) AF: 0.00 AC: 0 AN: 26253

American (AMR) AF: 0.00 AC: 0 AN: 33887

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19114

East Asian (EAS) AF: 0.00 AC: 0 AN: 29868

South Asian (SAS) AF: 0.00 AC: 0 AN: 52189

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39641

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.0000227 AC: 19 AN: 835827

Other (OTH) AF: 0.00 AC: 0 AN: 45697

GnomAD4 genome AF: 0.0000354 AC: 4 AN: 112846 Hom.: 0 Cov.: 24 AF XY: 0.0000571 AC XY: 2 AN XY: 35006

African (AFR) AF: 0.00 AC: 0 AN: 31084

American (AMR) AF: 0.00 AC: 0 AN: 10785

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00 AC: 0 AN: 2754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6271

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53276

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000340

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Creatine transporter deficiency (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.2
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.73	N
PhyloP100		-2.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.070
Sift	Benign	0.23	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.072
MutPred		0.41		Loss of catalytic residue at V95 (P = 0.0665)
MVP		0.32
MPC		1.0
ClinPred		0.030	T
GERP RS		-1.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.068
gMVP		0.31
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782040427; hg19: chrX-152955850; COSMIC: COSV53473019; COSMIC: COSV53473019;