chr1-111776126-G-A

Position:

chr1-111776126-G-A

Variant summary

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

The NM_001378969.1(KCND3):c.1919C>T(p.Thr640Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000239 in 1,461,890 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). Synonymous variant affecting the same amino acid position (i.e. T640T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

KCND3
NM_001378969.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.42

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]

KCND3 links:

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 gene, where missense usually causes diseases (based on misZ statistic), KCND3. . Gene score misZ: 3.8545 (greater than the threshold 3.09). Trascript score misZ: 4.8782 (greater than threshold 3.09). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. GenCC has associacion of the gene with spinocerebellar ataxia type 19/22, Brugada syndrome 1, Brugada syndrome 9.

BP4

Computational evidence support a benign effect (MetaRNN=0.18458277).

BP6

Variant 1-111776126-G-A is Benign according to our data. Variant chr1-111776126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1782617.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1 link	c.1919C>T	p.Thr640Met	missense_variant	8/8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCND3	ENST00000302127.5 link	c.1919C>T	p.Thr640Met	missense_variant	8/8	5	NM_001378969.1	ENSP00000306923.4	Q9UK17-1
KCND3	ENST00000315987.6 link	c.1919C>T	p.Thr640Met	missense_variant	8/8	1		ENSP00000319591.2	Q9UK17-1
KCND3	ENST00000369697.5 link	c.1862C>T	p.Thr621Met	missense_variant	6/6	1		ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251234

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2023

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

Spinocerebellar ataxia type 19/22

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 640 of the KCND3 protein (p.Thr640Met). This variant is present in population databases (rs752589615, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCND3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1782617). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.40

N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.029

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.86

.;P;.

Vest4

0.35

MutPred

0.14

.;Loss of glycosylation at T640 (P = 0.0319);.;

MVP

0.54

MPC

0.89

ClinPred

0.25

GERP RS

5.6

Varity_R

0.093

gMVP

0.58

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.

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