rs587777631

chr7-120732997-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_012281.3(KCND2):c.1210G>A(p.Val404Met) 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCND2 NM_012281.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 9.96

Genes affected

KCND2 (HGNC:6238): (potassium voltage-gated channel subfamily D member 2) 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 mediates a rapidly inactivating, A-type outward potassium current which is not under the control of the N terminus as it is in Shaker channels. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_012281.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCND2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 7-120732997-G-A is Pathogenic according to our data. Variant chr7-120732997-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 144007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND2	NM_012281.3	c.1210G>A	p.Val404Met	missense_variant	2/6	ENST00000331113.9
KCND2	XM_047420346.1	c.1210G>A	p.Val404Met	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND2	ENST00000331113.9	c.1210G>A	p.Val404Met	missense_variant	2/6	1	NM_012281.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.1210G>A (p.V404M) alteration is located in exon 2 (coding exon 2) of the KCND2 gene. This alteration results from a G to A substitution at nucleotide position 1210, causing the valine (V) at amino acid position 404 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported as de novo in multiple unrelated individuals with KCND2-related neurodevelopmental disorder (Lee, 2014; Zhang, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Overall, functional studies show aberrant channel activity in vitro (Lee, 2014; Lin, 2018; Zhang, 2021; Bavan, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early myoclonic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCND2 protein function (PMID: 29581270). This variant has been observed to be de novo in a family affected with seizures, autism and language delay (PMID: 24501278, Invitae). ClinVar contains an entry for this variant (Variation ID: 144007). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 404 of the KCND2 protein (p.Val404Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jul 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.66		Gain of helix (P = 0.0082);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.98

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

Other links and lift over

dbSNP: rs587777631; hg19: chr7-120373051;