X-153688582-A-G

Position:

• chrX-153688582-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005629.4(SLC6A8):​c.8A>G​(p.Lys3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 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)
  • Exomes 𝑓: 0.0000011 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.937

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16235435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.8A>G	p.Lys3Arg	missense_variant	1/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.8A>G	p.Lys3Arg	missense_variant	1/13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.8A>G	p.Lys3Arg	missense_variant	1/13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5	c.-3+233T>C		intron_variant		3		ENSP00000401542.1
PNCK	ENST00000480693.1	n.64+233T>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000109 AC: 1 AN: 921450 Hom.: 0 Cov.: 22 AF XY: 0.00000348 AC XY: 1 AN XY: 287438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000586

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.15		Loss of ubiquitination at K3 (P = 0.0134);
MVP		0.26
MPC		1.0
ClinPred		0.28	T
GERP RS		2.6
Varity_R		0.13
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: rs2091435821; hg19: chrX-152954037;