NM_005629.4:c.25G>T

Variant names:

• chrX-153688599-G-T
• rs2091436097
• NM_005629.4:c.25G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005629.4(SLC6A8):​c.25G>T​(p.Gly9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 950,416 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. G9V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.895
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17451563).

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.25G>T	p.Gly9Cys	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.25G>T	p.Gly9Cys	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.25G>T	p.Gly9Cys	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.25G>T	p.Gly9Cys	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.25G>T	p.Gly9Cys	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 950416 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 301832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19491

American (AMR) AF: 0.00 AC: 0 AN: 18150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15215

East Asian (EAS) AF: 0.00 AC: 0 AN: 18491

South Asian (SAS) AF: 0.00 AC: 0 AN: 41564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2486

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 764423

Other (OTH) AF: 0.00 AC: 0 AN: 38170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.20
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.90
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.096
Sift	Benign	0.14	T
Sift4G	Uncertain	0.010	D
Polyphen		0.053	B
Vest4		0.25
MutPred		0.35		Loss of loop (P = 0.0112)
MVP		0.23
MPC		1.6
ClinPred		0.23	T
GERP RS		1.7
PromoterAI		-0.018	Neutral
Varity_R		0.18
gMVP		0.43
Mutation Taster		=93/7	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: rs2091436097; hg19: chrX-152954054;