rs1060502811

Variant names:

• chrX-153695096-C-T
• rs1060502811
• NM_005629.4:c.1790C>T

Variant summary

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

The NM_005629.4(SLC6A8):​c.1790C>T​(p.Pro597Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P597P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1790C>T	p.Pro597Leu	missense_variant	Exon 13 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1760C>T	p.Pro587Leu	missense_variant	Exon 13 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1445C>T	p.Pro482Leu	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.1790C>T	p.Pro597Leu	missense_variant	Exon 13 of 13	1	NM_005629.4	ENSP00000253122.5
SLC6A8	ENST00000430077.6	c.1445C>T	p.Pro482Leu	missense_variant	Exon 13 of 13	2		ENSP00000403041.2
SLC6A8	ENST00000485324.1	n.2097C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Creatine transporter deficiency Uncertain:1

Oct 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SLC6A8-related disease. This sequence change replaces proline with leucine at codon 597 of the SLC6A8 protein (p.Pro597Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	0.81	L;.
PhyloP100		4.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.50
MutPred		0.67		Gain of MoRF binding (P = 0.0648);.;
MVP		0.84
MPC		0.66
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.96
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060502811; hg19: chrX-152960551;