Variant chrX-48966648-A-G 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.1397T>C(p.Leu466Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,207,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 2 hem. )

Consequence

KCND1
NM_004979.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14799613).

BS2

High Hemizygotes in GnomAdExome4 at 2 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	Protein	UniProt
KCND1	NM_004979.6 linkuse as main transcript	c.1397T>C	p.Leu466Pro	missense_variant	4/6	ENST00000218176.4	NP_004970.3	Q9NSA2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCND1	ENST00000218176.4 linkuse as main transcript	c.1397T>C	p.Leu466Pro	missense_variant	4/6	1	NM_004979.6	ENSP00000218176.3	Q9NSA2-1
KCND1	ENST00000376477.5 linkuse as main transcript	c.266T>C	p.Leu89Pro	missense_variant	3/5	2		ENSP00000365660.1	Q9NSA2-2
KCND1	ENST00000419374.1 linkuse as main transcript	c.110T>C	p.Leu37Pro	missense_variant	1/2	3		ENSP00000413989.1	H7C3V4

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110975

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33169

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000759

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

GnomAD3 exomes

AF:

0.0000222

AC:

AN:

179950

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000405

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1096990

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

362406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110975

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33169

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000759

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

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

Sep 08, 2024

The c.1397T>C (p.L466P) alteration is located in exon 4 (coding exon 4) of the KCND1 gene. This alteration results from a T to C substitution at nucleotide position 1397, causing the leucine (L) at amino acid position 466 to be replaced by a proline (P). 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

0.096

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;T

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.098

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0020

.;B

Vest4

0.27

MutPred

0.47

.;Gain of disorder (P = 0.0261);

MVP

0.96

MPC

0.081

ClinPred

0.10

GERP RS

4.5

Varity_R

0.41

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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