1-111982463-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001378969.1(KCND3):c.264C>T(p.Pro88Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,612,354 control chromosomes in the GnomAD database, including 10,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 618 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9567 hom. )

Consequence

KCND3
NM_001378969.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.11

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-111982463-G-A is Benign according to our data. Variant chr1-111982463-G-A is described in ClinVar as Benign. ClinVar VariationId is 129314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1 link	c.264C>T	p.Pro88Pro	synonymous_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.264C>T	p.Pro88Pro	synonymous_variant	Exon 2 of 8	5	NM_001378969.1	ENSP00000306923.4		Q9UK17-1

Frequencies

GnomAD3 genomes

AF:

0.0823

AC:

12522

AN:

152126

Hom.:

618

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0630

Gnomad ASJ

AF:

0.0734

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0561

Gnomad FIN

AF:

0.0646

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.0727

GnomAD2 exomes

AF:

0.0842

AC:

21137

AN:

251016

AF XY:

0.0866

show subpopulations

Gnomad AFR exome

AF:

0.0463

Gnomad AMR exome

AF:

0.0415

Gnomad ASJ exome

AF:

0.0738

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0660

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.0871

GnomAD4 exome

AF:

0.109

AC:

159107

AN:

1460110

Hom.:

9567

Cov.:

AF XY:

0.108

AC XY:

78351

AN XY:

725930

show subpopulations

African (AFR)

AF:

0.0423

AC:

1413

AN:

33438

American (AMR)

AF:

0.0442

AC:

1974

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0762

AC:

1987

AN:

26088

East Asian (EAS)

AF:

0.000883

AC:

AN:

39636

South Asian (SAS)

AF:

0.0645

AC:

5557

AN:

86214

European-Finnish (FIN)

AF:

0.0698

AC:

3729

AN:

53390

Middle Eastern (MID)

AF:

0.0746

AC:

430

AN:

5766

European-Non Finnish (NFE)

AF:

0.125

AC:

138278

AN:

1110584

Other (OTH)

AF:

0.0946

AC:

5704

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9532

19064

28596

38128

47660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4832

9664

14496

19328

24160

<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:

0.0822

AC:

12522

AN:

152244

Hom.:

618

Cov.:

AF XY:

0.0792

AC XY:

5891

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0459

AC:

1906

AN:

41562

American (AMR)

AF:

0.0629

AC:

962

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0734

AC:

255

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5166

South Asian (SAS)

AF:

0.0557

AC:

268

AN:

4812

European-Finnish (FIN)

AF:

0.0646

AC:

685

AN:

10608

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8176

AN:

68006

Other (OTH)

AF:

0.0724

AC:

153

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

603

1205

1808

2410

3013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.103

Hom.:

792

Bravo

AF:

0.0813

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.123

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Sep 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 23, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Apr 05, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Jun 18, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.9

(source)

DANN

Benign

0.85

PhyloP100

-3.1

PromoterAI

0.0087

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(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