1-111776247-C-T

Position:

chr1-111776247-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001378969.1(KCND3):c.1798G>A(p.Gly600Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,968 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G600A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:1

Conservation

PhyloP100: 1.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	8/8	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.1798G>A	p.Gly600Arg	missense_variant	8/8	5	NM_001378969.1	ENSP00000306923.4	Q9UK17-1
KCND3	ENST00000315987.6 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	8/8	1		ENSP00000319591.2	Q9UK17-1
KCND3	ENST00000369697.5 linkuse as main transcript	c.1741G>A	p.Gly581Arg	missense_variant	6/6	1		ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250980

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000985

AC:

144

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000446

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) In our internal patient population, this variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21349352, 26016905) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2024	Reported in at least one individual with Brugada syndrome and sudden unexplained death (PMID: 22457051); Published functional studies suggest a damaging effect as this variant significantly increased peak current density and slowed transient outward current inactivation (PMID: 22457051); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22840528, 29053796, 30662450, 22457051) -

Brugada syndrome 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Spinocerebellar ataxia type 19/22;C4225340:Brugada syndrome 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 30, 2021

- -

Spinocerebellar ataxia type 19/22

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 600 of the KCND3 protein (p.Gly600Arg). This variant is present in population databases (rs149344567, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 21349352, 22457051). ClinVar contains an entry for this variant (Variation ID: 192254). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCND3 function (PMID: 21349352, 22457051, 26016905). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

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

0.12

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T;.

Eigen

Benign

-0.0046

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.76

.;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.90

.;L;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.38

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.19

.;B;.

Vest4

0.71

MutPred

0.27

.;Loss of ubiquitination at K596 (P = 0.0175);.;

MVP

0.92

MPC

1.1

ClinPred

0.082

GERP RS

5.6

Varity_R

0.13

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: 31

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