1-111777089-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001378969.1(KCND3):​c.1703G>A​(p.Arg568His) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R568C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.90
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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, Brugada syndrome 1, Brugada syndrome 9.
BP4
Computational evidence support a benign effect (MetaRNN=0.12633142).
BP6
Variant 1-111777089-C-T is Benign according to our data. Variant chr1-111777089-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533722.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCND3NM_001378969.1 linkc.1703G>A p.Arg568His missense_variant Exon 7 of 8 ENST00000302127.5 NP_001365898.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCND3ENST00000302127.5 linkc.1703G>A p.Arg568His missense_variant Exon 7 of 8 5 NM_001378969.1 ENSP00000306923.4 Q9UK17-1
KCND3ENST00000315987.6 linkc.1703G>A p.Arg568His missense_variant Exon 7 of 8 1 ENSP00000319591.2 Q9UK17-1
KCND3ENST00000369697.5 linkc.1646G>A p.Arg549His missense_variant Exon 5 of 6 1 ENSP00000358711.1 Q9UK17-2
KCND3ENST00000703640.1 linkn.2337G>A non_coding_transcript_exon_variant Exon 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251364
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000792
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000101
AC:
148
AN:
1461722
Hom.:
0
Cov.:
32
AF XY:
0.000100
AC XY:
73
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000121
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000965
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 04, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Cardiovascular phenotype Benign:1
Feb 26, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Spinocerebellar ataxia type 19/22 Benign:1
Dec 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
.;T;.
Eigen
Benign
-0.0056
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.88
.;D;D
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Uncertain
0.15
D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.15
N;N;N
REVEL
Benign
0.28
Sift
Benign
0.26
T;T;T
Sift4G
Benign
0.14
T;T;T
Polyphen
0.0070
.;B;.
Vest4
0.21
MVP
0.53
MPC
0.76
ClinPred
0.58
D
GERP RS
5.5
Varity_R
0.13
gMVP
0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200212002; hg19: chr1-112319711; COSMIC: COSV56175473; API