X-48966670-C-T

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

17

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]

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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 rank MANE Protein UniProt
KCND1NM_004979.6 linkc.1375G>A p.Gly459Ser missense_variant Exon 4 of 6 ENST00000218176.4 NP_004970.3 Q9NSA2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCND1ENST00000218176.4 linkc.1375G>A p.Gly459Ser missense_variant Exon 4 of 6 1 NM_004979.6 ENSP00000218176.3 Q9NSA2-1
KCND1ENST00000376477.5 linkc.244G>A p.Gly82Ser missense_variant Exon 3 of 5 2 ENSP00000365660.1 Q9NSA2-2
KCND1ENST00000419374.1 linkc.88G>A p.Gly30Ser missense_variant Exon 1 of 2 3 ENSP00000413989.1 H7C3V4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.00000556
AC:
1
AN:
179755
Hom.:
0
AF XY:
0.0000155
AC XY:
1
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:
16
AN:
1096396
Hom.:
0
Cov.:
30
AF XY:
0.0000249
AC XY:
9
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.:
22
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
0.19
DANN
Benign
0.56
DEOGEN2
Benign
0.32
.;T
FATHMM_MKL
Benign
0.068
N
LIST_S2
Benign
0.36
T;T
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.073
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.11
.;N
PrimateAI
Benign
0.30
T
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
T
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.

Other links and lift over

dbSNP: rs782679992; hg19: chrX-48823077; API