rs122453117

chrX-153691304-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005629.4(SLC6A8):c.395G>T(p.Gly132Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: SLC6A8 NM_005629.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant X-153691304-G-T is Pathogenic according to our data. Variant chrX-153691304-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11703.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-153691304-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	3/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	3/13
SLC6A8	NM_001142806.1	c.50G>T	p.Gly17Val	missense_variant, splice_region_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	3/13	1	NM_005629.4	P1
SLC6A8	ENST00000430077.6	c.50G>T	p.Gly17Val	missense_variant, splice_region_variant	3/13	2
SLC6A8	ENST00000466243.1	n.187G>T		non_coding_transcript_exon_variant	1/2	2
SLC6A8	ENST00000675713.1	n.149G>T		splice_region_variant, non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Creatine transporter deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 14, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.95		Gain of ubiquitination at K131 (P = 0.0693);.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.14		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: rs122453117; hg19: chrX-152956759;