rs977790637

chr9-2718301-T-Achr9-2718301-T-Cchr9-2718301-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_133497.4(KCNV2):c.562T>A(p.Trp188Arg) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W188C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNV2 NM_133497.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.00

Genes affected

KCNV2 (HGNC:19698): (potassium voltage-gated channel modifier subfamily V 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. This gene encodes a member of the potassium voltage-gated channel subfamily V. This member is identified as a 'silent subunit', and it does not form homomultimers, but forms heteromultimers with several other subfamily members. Through obligatory heteromerization, it exerts a function-altering effect on other potassium channel subunits. This protein is strongly expressed in pancreas and has a weaker expression in several other tissues. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_133497.4 (KCNV2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a topological_domain Extracellular (size 84) in uniprot entity KCNV2_HUMAN there are 28 pathogenic changes around while only 8 benign (78%) in NM_133497.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-2718303-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1468960.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 9-2718301-T-A is Pathogenic according to our data. Variant chr9-2718301-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438151.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-2718301-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNV2	NM_133497.4	c.562T>A	p.Trp188Arg	missense_variant	1/2	ENST00000382082.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNV2	ENST00000382082.4	c.562T>A	p.Trp188Arg	missense_variant	1/2	1	NM_133497.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

KCNV2-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The KCNV2 c.562T>A variant is predicted to result in the amino acid substitution p.Trp188Arg. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with KCNV2-related retinal cone dystrophy (Table S2, Carss et al. 2017. PubMed ID: 28041643; Kiray et al. 2020. PubMed ID: 32154435; Table S2, Turro et al. 2020. PubMed ID: 32581362). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different nucleotide changes resulting in the same or different amino acid substitution have been reported to be causative for KCNV2-related retinal cone dystrophy (c.562T>C (p.Trp188Arg) in Table S5, Taylor et al. 2017. PubMed ID: 28341476; c.564G>C (p.Trp188Cys), Wu et al. 2006. PubMed ID: 16909397). Taken together, the c.562T>A (p.Trp188Arg) variant is interpreted as likely pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.86		Gain of methylation at W188 (P = 0.0148);
MVP		0.99
MPC		0.16
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.99

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: rs977790637; hg19: chr9-2718301;