Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The ENST00000302127.5(KCND3):c.1354G>A(p.Glu452Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,611,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KCND3
ENST00000302127.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.58

Publications

1 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 -15 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=0.014005572).

BP6

Variant 1-111780707-C-T is Benign according to our data. Variant chr1-111780707-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000302127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCND3	NM_001378969.1	MANE Select	c.1354G>A	p.Glu452Lys	missense	Exon 4 of 8	NP_001365898.1
KCND3	NM_004980.5		c.1354G>A	p.Glu452Lys	missense	Exon 4 of 8	NP_004971.2
KCND3	NM_001378970.1		c.1354G>A	p.Glu452Lys	missense	Exon 4 of 7	NP_001365899.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1354G>A	p.Glu452Lys	missense	Exon 4 of 8	ENSP00000306923.4
KCND3	ENST00000315987.6	TSL:1	c.1354G>A	p.Glu452Lys	missense	Exon 4 of 8	ENSP00000319591.2
KCND3	ENST00000369697.5	TSL:1	c.1354G>A	p.Glu452Lys	missense	Exon 3 of 6	ENSP00000358711.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000577

AC:

142

AN:

246220

AF XY:

0.000482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000120

AC:

175

AN:

1458810

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

725182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00342

AC:

152

AN:

44444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

85042

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1110772

Other (OTH)

AF:

0.0000332

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000112

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00111

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000341

Hom.:

Bravo

AF:

0.000246

ExAC

AF:

0.000469

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

KCND3-related disorder (1)

not specified (1)

Primary dilated cardiomyopathy (1)

Spinocerebellar ataxia type 19/22 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.051

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.8

PhyloP100

4.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.75

REVEL

Uncertain

0.47

Sift

Benign

0.45

Sift4G

Benign

0.79

Polyphen

0.66

Vest4

0.71

MutPred

0.34

Gain of ubiquitination at E452 (P = 0.0051)

MVP

0.86

MPC

0.61

ClinPred

0.075

GERP RS

5.3

Varity_R

0.20

gMVP

0.85

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs200532657

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over