rs146409435

Variant names:

• chr14-90184137-G-A
• rs146409435
• NM_022054.4:c.361G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022054.4(KCNK13):​c.361G>A​(p.Val121Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNK13 NM_022054.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73
• Publications: 0 publications found

Genes affected

KCNK13 (HGNC:6275): (potassium two pore domain channel subfamily K member 13) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a potassium channel containing two pore-forming domains. This protein is an open channel that can be stimulated by arachidonic acid and inhibited by the anesthetic halothane. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08364114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022054.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK13	NM_022054.4	MANE Select	c.361G>A	p.Val121Ile	missense	Exon 2 of 2	NP_071337.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK13	ENST00000282146.5	TSL:1 MANE Select	c.361G>A	p.Val121Ile	missense	Exon 2 of 2	ENSP00000282146.4	Q9HB14
	KCNK13	ENST00000954166.1		c.406G>A	p.Val136Ile	missense	Exon 3 of 3	ENSP00000624225.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251172 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726902

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111624

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.57
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.72	N
PhyloP100		2.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.093
Sift	Benign	0.58	T
Sift4G	Benign	0.64	T
Polyphen		0.0030	B
Vest4		0.053
MutPred		0.47		Gain of catalytic residue at V121 (P = 0)
MVP		0.36
MPC		0.19
ClinPred		0.043	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.55
Mutation Taster		=96/4	polymorphism

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: rs146409435; hg19: chr14-90650481; COSMIC: COSV56416667;