X-153694836-G-C

Variant names:

• chrX-153694836-G-C
• rs2872524
• NM_005629.4:c.1714G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005629.4(SLC6A8):​c.1714G>C​(p.Val572Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V572M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1714G>C	p.Val572Leu	missense	Exon 12 of 13	NP_005620.1
	SLC6A8	NM_001142805.2		c.1684G>C	p.Val562Leu	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1369G>C	p.Val457Leu	missense	Exon 12 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.1714G>C	p.Val572Leu	missense	Exon 12 of 13	ENSP00000253122.5
	SLC6A8	ENST00000955775.1		c.1711G>C	p.Val571Leu	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1705G>C	p.Val569Leu	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094605 Hom.: 0 Cov.: 38 AF XY: 0.00000277 AC XY: 1 AN XY: 360917

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 35024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30170

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39983

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3371

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840748

Other (OTH) AF: 0.00 AC: 0 AN: 45917

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.54
Sift	Benign	0.031	D
Sift4G	Uncertain	0.034	D
Polyphen		0.97	D
Vest4		0.28
MutPred		0.69		Gain of glycosylation at P573 (P = 0.379)
MVP		0.79
MPC		0.40
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.80
Mutation Taster		=80/20	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: rs2872524; hg19: chrX-152960291;