rs754759010

chr1-111776121-T-Achr1-111776121-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001378969.1(KCND3):c.1924A>T(p.Ile642Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,894 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.09

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCND3
• BP4: Computational evidence support a benign effect (MetaRNN=0.1795637).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND3	NM_001378969.1	c.1924A>T	p.Ile642Phe	missense_variant	8/8	ENST00000302127.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND3	ENST00000302127.5	c.1924A>T	p.Ile642Phe	missense_variant	8/8	5	NM_001378969.1	P3
KCND3	ENST00000315987.6	c.1924A>T	p.Ile642Phe	missense_variant	8/8	1		P3
KCND3	ENST00000369697.5	c.1867A>T	p.Ile623Phe	missense_variant	6/6	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251246 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2022

The p.I642F variant (also known as c.1924A>T), located in coding exon 7 of the KCND3 gene, results from an A to T substitution at nucleotide position 1924. The isoleucine at codon 642 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 19/22 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2017

This sequence change replaces isoleucine with phenylalanine at codon 642 of the KCND3 protein (p.Ile642Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs754759010, ExAC 0.01%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCND3-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	-0.041
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.15	.;B;.
Vest4		0.54
MutPred		0.11		.;Loss of helix (P = 0.079);.;
MVP		0.68
MPC		0.66
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.58

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: rs754759010; hg19: chr1-112318743;