14-88185722-C-T

Variant summary

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

The NM_138317.3(KCNK10):c.1445G>A(p.Arg482Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R482W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: KCNK10 NM_138317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

Genes affected

KCNK10 (HGNC:6273): (potassium two pore domain channel subfamily K member 10) The protein encoded by this gene belongs to the family of potassium channel proteins containing two pore-forming P domains. This channel is an open rectifier which primarily passes outward current under physiological K+ concentrations, and is stimulated strongly by arachidonic acid and to a lesser degree by membrane stretching, intracellular acidification, and general anaesthetics. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Sep 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=0.17622238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK10	NM_138317.3	c.1445G>A	p.Arg482Gln	missense_variant	7/7	ENST00000319231.10
KCNK10	NM_138318.3	c.1445G>A	p.Arg482Gln	missense_variant	7/7
KCNK10	NM_021161.5	c.1430G>A	p.Arg477Gln	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK10	ENST00000319231.10	c.1445G>A	p.Arg482Gln	missense_variant	7/7	1	NM_138317.3	P1
KCNK10	ENST00000312350.9	c.1445G>A	p.Arg482Gln	missense_variant	7/7	1
KCNK10	ENST00000340700.9	c.1430G>A	p.Arg477Gln	missense_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251496 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461894 Hom.: 0 Cov.: 39 AF XY: 0.0000509 AC XY: 37 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74262

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.1445G>A (p.R482Q) alteration is located in exon 7 (coding exon 7) of the KCNK10 gene. This alteration results from a G to A substitution at nucleotide position 1445, causing the arginine (R) at amino acid position 482 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.0078	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0084	T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.79	P;.;.
Vest4		0.24
MutPred		0.25		Gain of catalytic residue at I472 (P = 0.0143);.;.;
MVP		0.94
MPC		0.65
ClinPred		0.062	T
GERP RS		5.7
Varity_R		0.19
gMVP		0.26

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: rs781600628; hg19: chr14-88652066; COSMIC: COSV56648735;