rs2091436339

Variant names:

• chrX-153688625-G-C
• rs2091436339
• NM_005629.4:c.51G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005629.4(SLC6A8):​c.51G>C​(p.Glu17Asp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0480
• 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]

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 6 uncertain in NM_005629.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22201383).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.51G>C	p.Glu17Asp	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.51G>C	p.Glu17Asp	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.51G>C	p.Glu17Asp	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.51G>C	p.Glu17Asp	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.51G>C	p.Glu17Asp	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.048
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.078	T
Polyphen		0.78	P
Vest4		0.090
MutPred		0.14		Gain of glycosylation at S14 (P = 0.1199)
MVP		0.43
MPC		1.1
ClinPred		0.13	T
GERP RS		0.36
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.9
Varity_R		0.19
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2091436339; hg19: chrX-152954080;