Variant X-48966670-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_004979.6(KCND1):c.1375G>A(p.Gly459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,096,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000015 ( 0 hom. 9 hem. )

Consequence

KCND1
NM_004979.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0920

Variant links:

Genes affected

KCND1 (HGNC:6237): (potassium voltage-gated channel subfamily D member 1) This gene encodes a multipass membrane protein that comprises the pore subunit of the voltage-gated A-type potassium channel, which functions in the repolarization of membrane action potentials. Activity of voltage-gated potassium channels is important in a number of physiological processes, among them the regulation of neurotransmitter release, heart rate, insulin secretion, and smooth muscle contraction. [provided by RefSeq, Aug 2013]

KCND1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07347214).

BS2

High Hemizygotes in GnomAdExome4 at 9 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND1	NM_004979.6 linkuse as main transcript	c.1375G>A	p.Gly459Ser	missense_variant	4/6	ENST00000218176.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND1	ENST00000218176.4 linkuse as main transcript	c.1375G>A	p.Gly459Ser	missense_variant	4/6	1	NM_004979.6	P1	Q9NSA2-1
KCND1	ENST00000376477.5 linkuse as main transcript	c.244G>A	p.Gly82Ser	missense_variant	3/5	2			Q9NSA2-2
KCND1	ENST00000419374.1 linkuse as main transcript	c.91G>A	p.Gly31Ser	missense_variant	1/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000556

AC:

AN:

179755

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000543

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1096396

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000223

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.1375G>A (p.G459S) alteration is located in exon 4 (coding exon 4) of the KCND1 gene. This alteration results from a G to A substitution at nucleotide position 1375, causing the glycine (G) at amino acid position 459 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.19

DANN

Benign

0.56

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.22

Sift

Benign

0.48

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0050

.;B

Vest4

0.073

MutPred

0.23

.;Loss of catalytic residue at G459 (P = 0.0124);

MVP

0.83

MPC

0.054

ClinPred

0.014

GERP RS

-1.9

Varity_R

0.052

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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