chrX-153694552-C-G

Variant names:

• chrX-153694552-C-G
• NM_005629.4:c.1515C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005629.4(SLC6A8):​c.1515C>G​(p.Asp505Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.75

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32609528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1515C>G	p.Asp505Glu	missense_variant	Exon 11 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1485C>G	p.Asp495Glu	missense_variant	Exon 11 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1170C>G	p.Asp390Glu	missense_variant	Exon 11 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1515C>G	p.Asp505Glu	missense_variant	Exon 11 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Creatine transporter deficiency Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A8 protein function. This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 505 of the SLC6A8 protein (p.Asp505Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.075
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T;.;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Uncertain	0.29
Sift	Benign	0.048	D;T;T
Sift4G	Benign	0.10	T;T;D
Polyphen		0.81	P;.;.
Vest4		0.19
MutPred		0.45		Loss of stability (P = 0.3484);.;.;
MVP		0.60
MPC		0.53
ClinPred		0.93	D
GERP RS		-8.1
Varity_R		0.32
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152960007;