1-111776156-C-T

Position:

chr1-111776156-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001378969.1(KCND3):c.1889G>A(p.Arg630Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,008 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.26

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 -5 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=0.12241191).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1 linkuse as main transcript	c.1889G>A	p.Arg630Gln	missense_variant	8/8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5 linkuse as main transcript	c.1889G>A	p.Arg630Gln	missense_variant	8/8	5	NM_001378969.1	ENSP00000306923	P3	Q9UK17-1
KCND3	ENST00000315987.6 linkuse as main transcript	c.1889G>A	p.Arg630Gln	missense_variant	8/8	1		ENSP00000319591	P3	Q9UK17-1
KCND3	ENST00000369697.5 linkuse as main transcript	c.1832G>A	p.Arg611Gln	missense_variant	6/6	1		ENSP00000358711	A1	Q9UK17-2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251314

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 22, 2024

Variant summary: KCND3 c.1889G>A (p.Arg630Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1889G>A in individuals affected with Spinocerebellar Ataxia Type 19/22 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 934670). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 15, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.R630Q variant (also known as c.1889G>A), located in coding exon 7 of the KCND3 gene, results from a G to A substitution at nucleotide position 1889. The arginine at codon 630 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 19/22

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2023

This variant is present in population databases (rs774713377, gnomAD 0.009%). 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 934670). This variant has not been reported in the literature in individuals affected with KCND3-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 630 of the KCND3 protein (p.Arg630Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;.

Eigen

Benign

-0.089

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.90

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

0.010

N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.47

.;P;.

Vest4

0.10

MutPred

0.11

.;Gain of glycosylation at P625 (P = 0.1256);.;

MVP

0.91

MPC

0.51

ClinPred

0.16

GERP RS

5.8

Varity_R

0.12

gMVP

0.46

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