rs866544148

Variant names:

• chr1-111982683-G-A
• rs866544148
• NM_001378969.1:c.44C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001378969.1(KCND3):​c.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A15T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.19

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCND3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.8545 (above the threshold of 3.09). Trascript score misZ: 4.8782 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 19/22, Brugada syndrome 1, Brugada syndrome 9.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.44C>T	p.Ala15Val	missense_variant	Exon 2 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.44C>T	p.Ala15Val	missense_variant	Exon 2 of 8	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1457378 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725162

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: 0.00

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Nov 13, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Aug 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A15V variant (also known as c.44C>T), located in coding exon 1 of the KCND3 gene, results from a C to T substitution at nucleotide position 44. The alanine at codon 15 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.49
MVP		0.95
MPC		2.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.80

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: rs866544148; hg19: chr1-112525305; COSMIC: COSV105120634;