9-2729470-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_133497.4(KCNV2):c.1381G>A(p.Gly461Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,613,746 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

KCNV2
NM_133497.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.92

Variant links:

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]

KCNV2 links:

PUM3 (HGNC:29676): (pumilio RNA binding family member 3) Enables RNA binding activity. Involved in regulation of protein ADP-ribosylation. Located in chromosome; endoplasmic reticulum; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

PUM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a short_sequence_motif Selectivity filter (size 5) in uniprot entity KCNV2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_133497.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 9-2729470-G-A is Pathogenic according to our data. Variant chr9-2729470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2729470-G-A is described in Lovd as [Pathogenic]. Variant chr9-2729470-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNV2	NM_133497.4 linkuse as main transcript	c.1381G>A	p.Gly461Arg	missense_variant	2/2	ENST00000382082.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNV2	ENST00000382082.4 linkuse as main transcript	c.1381G>A	p.Gly461Arg	missense_variant	2/2	1	NM_133497.4	P1
PUM3	ENST00000490444.2 linkuse as main transcript	c.*127-8938C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251346

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000262

AC:

383

AN:

1461642

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

166

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000329

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000145

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 461 of the KCNV2 protein (p.Gly461Arg). This variant is present in population databases (rs149648640, gnomAD 0.03%). This missense change has been observed in individual(s) with cone dystrophy with supernormal rod electroretinogram (PMID: 17896311, 18400204). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37247). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNV2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNV2 function (PMID: 23115240). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cone dystrophy with supernormal rod response

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The KCNV2 c.1381G>A (p.Gly461Arg) missense variant has been reported in at least four studies in which it is found in a total of 15 individuals affected with retinal cone dystrophy including six homozygotes (three of whom are independent) and nine compound heterozygotes (eight of whom are indepedent) (Wissinger et al. 2008; Wissinger et al. 2011; Friedburg et al. 2011; Fujinami et al. 2013). The p.Gly461Arg variant was absent from a total of 159 controls (Wissinger et al. 2008; Wissinger et al. 2011) and is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. The variant is present in a conserved residue in the Gly-Tyr-Gly motif, an important functional domain in the pore region of the protein. Functional studies conducted in COS7 cells showed that the variant protein is trafficked to the membrane and likely forms heteromeric channels; however, current flow through these channels was reduced relative to that through those formed with the wild type form of the protein (Smith et al. 2012). Based on the collective evidence, the p.Gly461Arg variant is classified as pathogenic for retinal cone dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

KCNV2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2022

The KCNV2 c.1381G>A variant is predicted to result in the amino acid substitution p.Gly461Arg. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with retinal cone dystrophy (Thiagalingam et al. 2007. PubMed ID: 17896311; Friedburg et al. 2011. PubMed ID: 21911584; Fujinami et al. 2013. PubMed ID: 23885164; Table S2 in Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-2729470-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37247). Given the evidence, we interpret c.1381G>A (p.Gly461Arg) as pathogenic. -

Nystagmus;C0497552:Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jan 24, 2018

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.55

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.95

Gain of methylation at G461 (P = 0.0489);

MVP

0.98

MPC

0.15

ClinPred

0.99

GERP RS

5.4

Varity_R

0.93

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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