1-111777089-C-G

Variant names:

• chr1-111777089-C-G
• rs200212002
• NM_001378969.1:c.1703G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378969.1(KCND3):​c.1703G>C​(p.Arg568Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: not found (cov: 32)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• spinocerebellar ataxia type 19/22

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• Brugada syndrome 9

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, neurodevelopmental disorder, Brugada syndrome 1, Brugada syndrome 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30943054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1703G>C	p.Arg568Pro	missense_variant	Exon 7 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1703G>C	p.Arg568Pro	missense_variant	Exon 7 of 8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1703G>C	p.Arg568Pro	missense_variant	Exon 7 of 8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1646G>C	p.Arg549Pro	missense_variant	Exon 5 of 6	1		ENSP00000358711.1
KCND3	ENST00000703640.1	n.2337G>C		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Dec 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R568P variant (also known as c.1703G>C), located in coding exon 6 of the KCND3 gene, results from a G to C substitution at nucleotide position 1703. The arginine at codon 568 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.51	D
PhyloP100		3.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.68	.;P;.
Vest4		0.46
MutPred		0.26		.;Loss of solvent accessibility (P = 0.0079);.;
MVP		0.68
MPC		0.78
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.30
gMVP		0.58
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs200212002; hg19: chr1-112319711;