14-88185936-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.1231G>A(p.Gly411Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNK10 NM_138317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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=0.20458299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK10	NM_138317.3	c.1231G>A	p.Gly411Ser	missense_variant	7/7	ENST00000319231.10
KCNK10	NM_138318.3	c.1231G>A	p.Gly411Ser	missense_variant	7/7
KCNK10	NM_021161.5	c.1216G>A	p.Gly406Ser	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK10	ENST00000319231.10	c.1231G>A	p.Gly411Ser	missense_variant	7/7	1	NM_138317.3	P1
KCNK10	ENST00000312350.9	c.1231G>A	p.Gly411Ser	missense_variant	7/7	1
KCNK10	ENST00000340700.9	c.1216G>A	p.Gly406Ser	missense_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151792 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251344 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461810 Hom.: 0 Cov.: 39 AF XY: 0.0000138 AC XY: 10 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151792 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74134

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Sep 07, 2022

The c.1231G>A (p.G411S) 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 1231, causing the glycine (G) at amino acid position 411 to be replaced by a serine (S). 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	0.086
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0050	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.81	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.43	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.81	P;.;.
Vest4		0.039
MutPred		0.24		Gain of phosphorylation at G406 (P = 0.023);.;.;
MVP		0.92
MPC		0.40
ClinPred		0.25	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.25

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: rs761281029; hg19: chr14-88652280;