rs149008060

Positions:

chr1-111780230-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001378969.1(KCND3):c.1456A>G(p.Thr486Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,584,728 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 7.42

Variant links:

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]

KCND3 links:

KCND3 (HGNC:):

KCND3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCND3. . Gene score misZ 3.8545 (greater than the threshold 3.09). Trascript score misZ 4.8782 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 19/22, Brugada syndrome 1, Brugada syndrome 9.

BP4

Computational evidence support a benign effect (MetaRNN=0.060301185).

BP6

Variant 1-111780230-T-C is Benign according to our data. Variant chr1-111780230-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415286.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr1-111780230-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1 linkuse as main transcript	c.1456A>G	p.Thr486Ala	missense_variant	5/8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCND3	ENST00000302127.5 linkuse as main transcript	c.1456A>G	p.Thr486Ala	missense_variant	5/8	5	NM_001378969.1	ENSP00000306923.4	Q9UK17-1
KCND3	ENST00000315987.6 linkuse as main transcript	c.1456A>G	p.Thr486Ala	missense_variant	5/8	1		ENSP00000319591.2	Q9UK17-1
KCND3	ENST00000369697.5 linkuse as main transcript	c.1456A>G	p.Thr486Ala	missense_variant	4/6	1		ENSP00000358711.1	Q9UK17-2
KCND3	ENST00000703640.1 linkuse as main transcript	n.2147A>G		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes

AF:

0.000751

AC:

114

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000612

AC:

126

AN:

206024

Hom.:

AF XY:

0.000648

AC XY:

AN XY:

109562

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000314

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000939

GnomAD4 exome

AF:

0.00109

AC:

1557

AN:

1432712

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

778

AN XY:

709168

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000222

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000233

Gnomad4 FIN exome

AF:

0.000213

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000750

AC:

114

AN:

152016

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000740

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000604

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2016	A variant of uncertain significance has been identified in the KCND3 gene. The T486A variant in the KCND3 has been observed in 2 unrelated individuals with early-onset atrial fibrillation and was absent from 432 control individuals (Olesen et al., 2013). Nevertheless, Giudicessi et al. (2011) observed the T486A variant in 1 ostensibly healthy control individual, and the Exome Aggregation Consortium (ExAC) data set reported T486A was observed in 44/16148 (0.27%) alleles from individuals of European background, indicating it may be a rare (benign) variant in this population. The T486A 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCND3: PP3, BS1 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 07, 2016	- -

KCND3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2019

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;T;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Uncertain

0.084

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.48

.;P;.

Vest4

0.68

MVP

0.83

MPC

0.64

ClinPred

0.055

GERP RS

5.0

Varity_R

0.32

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over