rs1181103233

Variant names:

• chrX-153695180-G-A
• rs1181103233
• NM_005629.4:c.1874G>A

Variant summary

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

The ENST00000253122.10(SLC6A8):​c.1874G>A​(p.Ser625Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000504 in 1,190,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000054 (0 hom. 22 hem.)
• Consequence: SLC6A8 ENST00000253122.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.18
• 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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09410134).
• BS2: High Hemizygotes in GnomAdExome4 at 22 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000253122.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1874G>A	p.Ser625Asn	missense	Exon 13 of 13	NP_005620.1
	SLC6A8	NM_001142805.2		c.1844G>A	p.Ser615Asn	missense	Exon 13 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1529G>A	p.Ser510Asn	missense	Exon 13 of 13	NP_001136278.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1874G>A	p.Ser625Asn	missense	Exon 13 of 13	ENSP00000253122.5
	SLC6A8	ENST00000430077.6	TSL:2	c.1529G>A	p.Ser510Asn	missense	Exon 13 of 13	ENSP00000403041.2
	SLC6A8	ENST00000485324.1	TSL:2	n.2181G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111621 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: 0.0000134 AC: 2 AN: 149653 AF XY: 0.00

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: 0.0000320

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000537 AC: 58 AN: 1079352 Hom.: 0 Cov.: 31 AF XY: 0.0000627 AC XY: 22 AN XY: 351154

African (AFR) AF: 0.0000386 AC: 1 AN: 25923

American (AMR) AF: 0.00 AC: 0 AN: 33225

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19048

East Asian (EAS) AF: 0.00 AC: 0 AN: 29221

South Asian (SAS) AF: 0.00 AC: 0 AN: 51694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3907

European-Non Finnish (NFE) AF: 0.0000661 AC: 55 AN: 832063

Other (OTH) AF: 0.0000441 AC: 2 AN: 45357

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111621 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33789

African (AFR) AF: 0.0000326 AC: 1 AN: 30667

American (AMR) AF: 0.00 AC: 0 AN: 10583

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53041

Other (OTH) AF: 0.00 AC: 0 AN: 1490

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Creatine deficiency syndrome 1 (1)
-	1	-	Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.16
Sift	Benign	0.45	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.22		Loss of disorder (P = 0.0673)
MVP		0.13
MPC		0.14
ClinPred		0.22	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.49
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs1181103233; hg19: chrX-152960635;