rs2872524

Positions:

• chrX-153694836-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_005629.4(SLC6A8):​c.1714G>A​(p.Val572Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,094,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V572V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000039 (0 hom. 14 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_005629.4
• BP6: Variant X-153694836-G-A is Benign according to our data. Variant chrX-153694836-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449188.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1714G>A	p.Val572Met	missense_variant	12/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1684G>A	p.Val562Met	missense_variant	12/13
SLC6A8	NM_001142806.1	c.1369G>A	p.Val457Met	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1714G>A	p.Val572Met	missense_variant	12/13	1	NM_005629.4	P1
SLC6A8	ENST00000430077.6	c.1369G>A	p.Val457Met	missense_variant	12/13	2
SLC6A8	ENST00000485324.1	n.2021G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000397 AC: 7 AN: 176255 Hom.: 0 AF XY: 0.0000481 AC XY: 3 AN XY: 62357

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000644

Gnomad NFE exome AF: 0.0000772

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 43 AN: 1094605 Hom.: 0 Cov.: 38 AF XY: 0.0000388 AC XY: 14 AN XY: 360917

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.000125

Gnomad4 NFE exome AF: 0.0000393

Gnomad4 OTH exome AF: 0.0000653

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000907 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2017

A variant of uncertain significance has been identified in the SLC6A8 gene. The V572M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V572M variant is observed in 6/35470 (0.02%) alleles from individuals of European background, including 3 unrelated hemizygous individuals in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V572M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However. in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Creatine transporter deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.40
MVP		0.92
MPC		0.61
ClinPred		0.40	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2872524; hg19: chrX-152960291;