rs142744204

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001378969.1(KCND3):c.641A>G(p.Lys214Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000298 in 1,613,754 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 0.00033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 4.90

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
spinocerebellar ataxia type 19/22
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Brugada syndrome 9
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCND3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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, neurodevelopmental disorder, Brugada syndrome 1, Brugada syndrome 9.

BP4

Computational evidence support a benign effect (MetaRNN=0.011372328).

BP6

Variant 1-111982086-T-C is Benign according to our data. Variant chr1-111982086-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222665.

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1 link	c.641A>G	p.Lys214Arg	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 link	c.641A>G	p.Lys214Arg	missense_variant	Exon 2 of 8	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000196

AC:

AN:

249806

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000355

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000295

AC:

431

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

217

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000356

AC:

396

AN:

1111988

Other (OTH)

AF:

0.000215

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000329

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41516

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5074

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a patient with features of cerebellar ataxia referred for whole exome sequencing; however, this variant was inherited from an unaffected mother (Coutelier et al., 2018); Reported in one ostensibly healthy control individual and in association with atrial fibrillation (Giudicessi et al., 2011; Mann et al., 2012); Published functional studies demonstrate no damaging effect (Mann et al., 2012); This variant is associated with the following publications: (PMID: 26220970, 23838598, 25175087, 25410959, 29482223, 22402074, 21349352) -

Spinocerebellar ataxia type 19/22

Uncertain:1Benign:1

Institute of Human Genetics, University Hospital of Duesseldorf

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 11, 2014

Blueprint Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 09, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCND3-related disorder

Uncertain:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KCND3 c.641A>G variant is predicted to result in the amino acid substitution p.Lys214Arg. This variant has been reported in individuals with episodic gait disorder, Brugada syndrome, or atrial fibrillation (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Mann SA et al 2012. PubMed ID: 22402074). However, this variant was also inherited from an unaffected parent of a proband with episodic gait disorder and was identified in controls for the Brugada syndrome study (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Giudicessi JR et al 2011. PubMed ID: 21349352). An in vitro study of this variant showed no change in cellular electrophysiology (Mann SA et al 2012. PubMed ID: 22402074). This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of autosomal dominant disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Benign:1

Dec 07, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.62

.;D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

.;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.0037

MutationAssessor

Benign

0.43

N;N;N

PhyloP100

4.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.89

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.18

MVP

0.78

MPC

1.2

ClinPred

0.034

GERP RS

5.5

Varity_R

0.12

gMVP

0.59

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over