Genetic Variant KCND1:p.Ile599Asn (chrX-48962729-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_004979.6(KCND1):c.1796T>A(p.Ile599Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,097,536 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

KCND1
NM_004979.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.22

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

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 rank	MANE	Protein	UniProt
KCND1	NM_004979.6 link	c.1796T>A	p.Ile599Asn	missense_variant	Exon 6 of 6	ENST00000218176.4	NP_004970.3	Q9NSA2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND1	ENST00000218176.4 link	c.1796T>A	p.Ile599Asn	missense_variant	Exon 6 of 6	1	NM_004979.6	ENSP00000218176.3		Q9NSA2-1
KCND1	ENST00000376477.5 link	c.665T>A	p.Ile222Asn	missense_variant	Exon 5 of 5	2		ENSP00000365660.1		Q9NSA2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000555

AC:

AN:

180334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65586

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097536

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362908

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1796T>A (p.I599N) alteration is located in exon 6 (coding exon 6) of the KCND1 gene. This alteration results from a T to A substitution at nucleotide position 1796, causing the isoleucine (I) at amino acid position 599 to be replaced by an asparagine (N). 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.78

MutPred

0.29

.;Loss of sheet (P = 0.0228);

MVP

0.93

MPC

0.44

ClinPred

0.93

GERP RS

5.0

Varity_R

0.90

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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