rs373570632

Variant names:

• chrX-153695194-G-A
• rs373570632
• NM_005629.4:c.1888G>A
• SLC6A8 p.Val630Met

Your query was ambiguous. Multiple possible variants found:

• chrX-153695194-G-A
• chrX-153695194-G-T
• chrX-153695194-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005629.4(SLC6A8):​c.1888G>A​(p.Val630Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,183,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V630L) has been classified as Uncertain significance. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000022 (0 hom. 9 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.68
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Orphanet

ACMG classification

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09061402).
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

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.1888G>A	p.Val630Met	missense	Exon 13 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1858G>A	p.Val620Met	missense	Exon 13 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1543G>A	p.Val515Met	missense	Exon 13 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.1888G>A	p.Val630Met	missense	Exon 13 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1885G>A	p.Val629Met	missense	Exon 13 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1879G>A	p.Val627Met	missense	Exon 13 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111320 Hom.: 0 Cov.: 23

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000212 AC: 3 AN: 141328 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000849

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000728

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000224 AC: 24 AN: 1072401 Hom.: 0 Cov.: 31 AF XY: 0.0000258 AC XY: 9 AN XY: 348479

African (AFR) AF: 0.00 AC: 0 AN: 25726

American (AMR) AF: 0.0000929 AC: 3 AN: 32301

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18971

East Asian (EAS) AF: 0.00 AC: 0 AN: 28692

South Asian (SAS) AF: 0.0000196 AC: 1 AN: 51138

European-Finnish (FIN) AF: 0.0000261 AC: 1 AN: 38294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3814

European-Non Finnish (NFE) AF: 0.0000217 AC: 18 AN: 828366

Other (OTH) AF: 0.0000222 AC: 1 AN: 45099

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111320 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33516

African (AFR) AF: 0.00 AC: 0 AN: 30579

American (AMR) AF: 0.00 AC: 0 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52956

Other (OTH) AF: 0.00 AC: 0 AN: 1487

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Creatine transporter deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Uncertain	0.041	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.59
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373570632;

hg19: chrX-152960649;

COSMIC: COSV99465752;

COSMIC: COSV99465752;