rs1557045828

Variant names:

• chrX-153695104-G-A
• rs1557045828
• NM_005629.4:c.1798G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005629.4(SLC6A8):​c.1798G>A​(p.Gly600Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. G600D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3883195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1798G>A	p.Gly600Ser	missense_variant	Exon 13 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1768G>A	p.Gly590Ser	missense_variant	Exon 13 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1453G>A	p.Gly485Ser	missense_variant	Exon 13 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1798G>A	p.Gly600Ser	missense_variant	Exon 13 of 13	1	NM_005629.4	ENSP00000253122.5
SLC6A8	ENST00000430077.6	c.1453G>A	p.Gly485Ser	missense_variant	Exon 13 of 13	2		ENSP00000403041.2
SLC6A8	ENST00000485324.1	n.2105G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.18e-7 AC: 1 AN: 1089799 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357021

African (AFR) AF: 0.00 AC: 0 AN: 26257

American (AMR) AF: 0.00 AC: 0 AN: 34477

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19209

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29912

South Asian (SAS) AF: 0.00 AC: 0 AN: 52745

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3937

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837906

Other (OTH) AF: 0.00 AC: 0 AN: 45712

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

Sep 05, 2017

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. This sequence change replaces glycine with serine at codon 600 of the SLC6A8 protein (p.Gly600Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC6A8-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.81	L;.
PhyloP100		4.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.26
Sift	Benign	0.50	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.13	B;.
Vest4		0.23
MutPred		0.73		Gain of helix (P = 0.1736);.;
MVP		0.62
MPC		0.28
ClinPred		0.56	D
GERP RS		5.3
Varity_R		0.21
gMVP		0.89
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1557045828; hg19: chrX-152960559;