rs1057521793

Positions:

• chr1-111787102-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001378969.1(KCND3):​c.1111G>A​(p.Gly371Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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]

LOC124904312 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001378969.1
• PM2: Very rare variant in population databases, with high coverage
• 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). GenCC has associacion of gene with spinocerebellar ataxia type 19/22, Brugada syndrome 1, Brugada syndrome 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-111787102-C-T is Pathogenic according to our data. Variant chr1-111787102-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 383943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1111G>A	p.Gly371Arg	missense_variant	3/8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1111G>A	p.Gly371Arg	missense_variant	3/8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1111G>A	p.Gly371Arg	missense_variant	3/8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1111G>A	p.Gly371Arg	missense_variant	2/6	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Duke University Health System Sequencing Clinic, Duke University Health System

Apr 20, 2023

- -

Brugada syndrome 9 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Jun 10, 2022

The c.1111G>A;p.(Gly371Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 383943; PMID: 31017293) - PS4_supporting. This variant is not present in population databases:rs1057521793, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 31017293 ) PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2023

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31017293) -

Spinocerebellar ataxia type 19/22 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Nov 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H;H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.91
MutPred		0.92		Gain of glycosylation at T367 (P = 0.1263);Gain of glycosylation at T367 (P = 0.1263);Gain of glycosylation at T367 (P = 0.1263);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.90
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs1057521793; hg19: chr1-112329724; COSMIC: COSV100137428;