rs868950793

Positions:

• chrX-153688666-C-A
• chrX-153688666-C-G
• chrX-153688666-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005629.4(SLC6A8):​c.92C>A​(p.Pro31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 969,025 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. 12/20 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. P31L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24598551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.92C>A	p.Pro31Gln	missense_variant	1/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.92C>A	p.Pro31Gln	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.92C>A	p.Pro31Gln	missense_variant	1/13	1	NM_005629.4	P1
PNCK	ENST00000458354.5	c.-3+149G>T		intron_variant		3
PNCK	ENST00000480693.1	n.64+149G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 969025 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 307807

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000129

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.19
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.022	D
Polyphen		0.82	P
Vest4		0.15
MutPred		0.22		Gain of catalytic residue at P31 (P = 0.0182);
MVP		0.32
MPC		1.1
ClinPred		0.24	T
GERP RS		2.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.17
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs868950793; hg19: chrX-152954121;