X-153688690-G-C

Variant names:

• chrX-153688690-G-C
• rs781997638
• NM_005629.4:c.116G>C

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.116G>C​(p.Gly39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,112,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000030 (0 hom. 1 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.896
• 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=0.085069716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.116G>C	p.Gly39Ala	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.116G>C	p.Gly39Ala	missense_variant	Exon 1 of 13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.116G>C	p.Gly39Ala	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5	c.-3+125C>G		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
PNCK	ENST00000480693.1	n.64+125C>G		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1	n.-33G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000917 AC: 1 AN: 108998 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 3 AN: 1003859 Hom.: 0 Cov.: 27 AF XY: 0.00000310 AC XY: 1 AN XY: 322117

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

African (AFR) AF: 0.000141 AC: 3 AN: 21259

American (AMR) AF: 0.00 AC: 0 AN: 24867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16421

East Asian (EAS) AF: 0.00 AC: 0 AN: 21968

South Asian (SAS) AF: 0.00 AC: 0 AN: 45822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3075

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 793366

Other (OTH) AF: 0.00 AC: 0 AN: 40957

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000917 AC: 1 AN: 109020 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32226

African (AFR) AF: 0.0000328 AC: 1 AN: 30506

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2593

East Asian (EAS) AF: 0.00 AC: 0 AN: 3359

South Asian (SAS) AF: 0.00 AC: 0 AN: 2620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5311

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51669

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000875 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.63
DEOGEN2	Benign	0.093	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.90
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.45	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.88	P
Vest4		0.12
MutPred		0.32		Loss of loop (P = 0.0804);
MVP		0.36
MPC		1.3
ClinPred		0.015	T
GERP RS		2.3
PromoterAI		-0.043	Neutral
Varity_R		0.076
gMVP		0.31
Mutation Taster		=91/9	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: rs781997638; hg19: chrX-152954145;