1-111982722-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_001378969.1(KCND3):c.5C>A(p.Ala2Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000976 in 1,602,190 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCND3
• BP6: Variant 1-111982722-G-T is Benign according to our data. Variant chr1-111982722-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr1-111982722-G-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND3	NM_001378969.1	c.5C>A	p.Ala2Glu	missense_variant	2/8	ENST00000302127.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND3	ENST00000302127.5	c.5C>A	p.Ala2Glu	missense_variant	2/8	5	NM_001378969.1	P3

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000530 AC: 122 AN: 230260 Hom.: 0 AF XY: 0.000417 AC XY: 53 AN XY: 126992

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000213

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.00101 AC: 1470 AN: 1449972 Hom.: 1 Cov.: 32 AF XY: 0.000949 AC XY: 685 AN XY: 721612

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000615

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74374

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.000428 AC: 51

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	A variant of uncertain significance has been identified in the KCND3 gene. The A2E variant has been reported in a patient with atrial fibrillation (Mann et al., 2012). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties and occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, functional studies showed that this variant behaved similarly to the wild type using in vitro electrophysiological studies (Mann et al., 2012). Finally, the Exome Aggregation Consortium reports A2E was observed in 45/20,744 (0.1%) alleles from individuals of European, non-Finnish background. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	Variant summary: KCND3 c.5C>A (p.Ala2Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 230260 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1600 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCND3 causing Spinocerebellar Ataxia Type 19/22 phenotype (6.3e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5C>A has been reported in the literature in individuals affected with atrial fibrillation, abnormality of the nervous system, primary electrical disease, Brugada syndrome and Long QT syndrome (Mann_2012, Retterer_2015, Proost_2017, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Spinocerebellar Ataxia Type 19/22. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCND3: PP2, PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Spinocerebellar ataxia type 19/22 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.75
MVP		0.99
MPC		1.6
ClinPred		0.10	T
GERP RS		5.4
Varity_R		0.63
gMVP		0.93

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: rs201340369; hg19: chr1-112525344; COSMIC: COSV56185457;