14-88185618-C-T

Variant names:

• chr14-88185618-C-T
• rs17762463
• NM_138317.3:c.1549G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138317.3(KCNK10):​c.1549G>A​(p.Ala517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,932 control chromosomes in the GnomAD database, including 53,615 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3843 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49772 hom.)
• Consequence: KCNK10 NM_138317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039073527).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK10	NM_138317.3	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	ENST00000319231.10	NP_612190.1
KCNK10	NM_138318.3	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7		NP_612191.1
KCNK10	NM_021161.5	c.1534G>A	p.Ala512Thr	missense_variant	Exon 7 of 7		NP_066984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK10	ENST00000319231.10	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	1	NM_138317.3	ENSP00000312811.5
KCNK10	ENST00000312350.9	c.1549G>A	p.Ala517Thr	missense_variant	Exon 7 of 7	1		ENSP00000310568.5
KCNK10	ENST00000340700.9	c.1534G>A	p.Ala512Thr	missense_variant	Exon 7 of 7	1		ENSP00000343104.5

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29849 AN: 152030 Hom.: 3844 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.205 AC: 51519 AN: 251264 AF XY: 0.208

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.0170

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.250 AC: 365890 AN: 1461784 Hom.: 49772 Cov.: 50 AF XY: 0.248 AC XY: 180093 AN XY: 727194

African (AFR) AF: 0.0498 AC: 1666 AN: 33480

American (AMR) AF: 0.120 AC: 5355 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7083 AN: 26132

East Asian (EAS) AF: 0.0104 AC: 413 AN: 39660

South Asian (SAS) AF: 0.106 AC: 9115 AN: 86258

European-Finnish (FIN) AF: 0.316 AC: 16859 AN: 53420

Middle Eastern (MID) AF: 0.222 AC: 1283 AN: 5768

European-Non Finnish (NFE) AF: 0.279 AC: 310086 AN: 1111954

Other (OTH) AF: 0.232 AC: 14030 AN: 60390

GnomAD4 genome AF: 0.196 AC: 29837 AN: 152148 Hom.: 3843 Cov.: 32 AF XY: 0.197 AC XY: 14662 AN XY: 74358

African (AFR) AF: 0.0574 AC: 2385 AN: 41534

American (AMR) AF: 0.164 AC: 2508 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3472

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5176

South Asian (SAS) AF: 0.0963 AC: 464 AN: 4816

European-Finnish (FIN) AF: 0.315 AC: 3329 AN: 10556

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19298 AN: 67982

Other (OTH) AF: 0.188 AC: 398 AN: 2114

Alfa AF: 0.246 Hom.: 17934

Bravo AF: 0.178

TwinsUK AF: 0.267 AC: 991

ALSPAC AF: 0.263 AC: 1015

ESP6500AA AF: 0.0647 AC: 285

ESP6500EA AF: 0.277 AC: 2382

ExAC AF: 0.207 AC: 25104

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.9
DANN	Benign	0.97
DEOGEN2	Benign	0.0044	T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.;.
PhyloP100		1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.84	T;T;T
Polyphen		0.043	B;.;.
Vest4		0.045
MPC		0.40
ClinPred		0.0061	T
GERP RS		3.5
Varity_R		0.056
gMVP		0.081
Mutation Taster		=97/3	polymorphism (auto)

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: rs17762463; hg19: chr14-88651962; COSMIC: COSV56650505;