rs782208622

Variant names:

• chrX-153693083-G-A
• rs782208622
• NM_005629.4:c.820G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153693083-G-A
• chrX-153693083-G-C

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.820G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 274 (p.Val274Met). This variant has been previously reported in one individual with hypotonia, global developmental delay, and microcephaly, but who was found to have normal urine creatine and guanidinoacetate levels on two separate occasions and a de novo variant in KAT6A as an alternate molecular cause of his symptoms (PMID 27133397) (BS2). In gnomAD v2.1.1, the highest population allele frequency is 0.00015 (14/91767 alleles) in the European (Non-Finnish) population and there are 4 hemizygotes across all populations, 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 0.559, 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: 4416002). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. 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 November 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549333/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000098 (0 hom. 33 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:3
• Conservation: PhyloP100: 1.88
• Publications: 0 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

Our verdict: Uncertain_significance. The variant received -4 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.820G>A	p.Val274Met	missense	Exon 5 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.820G>A	p.Val274Met	missense	Exon 5 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.475G>A	p.Val159Met	missense	Exon 5 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.820G>A	p.Val274Met	missense	Exon 5 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.820G>A	p.Val274Met	missense	Exon 5 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.820G>A	p.Val274Met	missense	Exon 5 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.0000532 AC: 6 AN: 112691 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000930

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: 0.0000940

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000714 AC: 13 AN: 182136 AF XY: 0.0000446

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: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000976 AC: 107 AN: 1096467 Hom.: 0 Cov.: 32 AF XY: 0.0000911 AC XY: 33 AN XY: 362203

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3573

European-Non Finnish (NFE) AF: 0.000106 AC: 89 AN: 841244

Other (OTH) AF: 0.000130 AC: 6 AN: 45994

GnomAD4 genome AF: 0.0000532 AC: 6 AN: 112691 Hom.: 0 Cov.: 24 AF XY: 0.0000861 AC XY: 3 AN XY: 34851

African (AFR) AF: 0.00 AC: 0 AN: 31050

American (AMR) AF: 0.0000930 AC: 1 AN: 10748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2781

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6231

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53206

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.0000642

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Creatine transporter deficiency (2)
-	-	1	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.72		Loss of sheet (P = 0.0817)
MVP		0.85
MPC		2.2
ClinPred		0.22	T
GERP RS		4.9
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.27
gMVP		0.58
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782208622; hg19: chrX-152958538;