dbSNP rs149008060: KCND3:p.Thr486Ala (chr1-111780230-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001378969.1(KCND3):c.1456A>G(p.Thr486Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,584,728 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 0.00075 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 7.42

Publications

8 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
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=0.060301185).

BP6

Variant 1-111780230-T-C is Benign according to our data. Variant chr1-111780230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415286.

BS2

High AC in GnomAd4 at 114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378969.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCND3	NM_001378969.1	MANE Select	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	NP_001365898.1	Q9UK17-1
KCND3	NM_004980.5		c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	NP_004971.2
KCND3	NM_001378970.1		c.1456A>G	p.Thr486Ala	missense	Exon 5 of 7	NP_001365899.1	Q9UK17-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	ENSP00000306923.4	Q9UK17-1
KCND3	ENST00000315987.6	TSL:1	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	ENSP00000319591.2	Q9UK17-1
KCND3	ENST00000369697.5	TSL:1	c.1456A>G	p.Thr486Ala	missense	Exon 4 of 6	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes

AF:

0.000751

AC:

114

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000612

AC:

126

AN:

206024

AF XY:

0.000648

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000939

GnomAD4 exome

AF:

0.00109

AC:

1557

AN:

1432712

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

778

AN XY:

709168

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33086

American (AMR)

AF:

0.000222

AC:

AN:

40626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

38844

South Asian (SAS)

AF:

0.000233

AC:

AN:

81618

European-Finnish (FIN)

AF:

0.000213

AC:

AN:

51564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.00132

AC:

1450

AN:

1096726

Other (OTH)

AF:

0.00106

AC:

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.000750

AC:

114

AN:

152016

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41480

American (AMR)

AF:

0.000197

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

67966

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000991

Hom.:

Bravo

AF:

0.000740

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000604

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

KCND3-related disorder (1)

Spinocerebellar ataxia type 19/22 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.060

MetaSVM

Uncertain

0.084

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.65

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.48

Vest4

0.68

MVP

0.83

MPC

0.64

ClinPred

0.055

GERP RS

5.0

Varity_R

0.32

gMVP

0.67

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over