rs12352254

Positions:

chr9-2729686-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_133497.4(KCNV2):c.1597C>G(p.Leu533Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,613,502 control chromosomes in the GnomAD database, including 9,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2708 hom., cov: 32)

Exomes 𝑓: 0.079 ( 6340 hom. )

Consequence

KCNV2
NM_133497.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.122

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004412204).

BP6

Variant 9-2729686-C-G is Benign according to our data. Variant chr9-2729686-C-G is described in ClinVar as [Benign]. Clinvar id is 262361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2729686-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNV2	NM_133497.4 linkuse as main transcript	c.1597C>G	p.Leu533Val	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.1597C>G	p.Leu533Val	missense_variant	2/2	1	NM_133497.4	P1
PUM3	ENST00000490444.2 linkuse as main transcript	c.*127-9154G>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22397

AN:

151938

Hom.:

2689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.330

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.0890

Gnomad EAS

AF:

0.0251

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.0705

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0745

Gnomad OTH

AF:

0.118

GnomAD3 exomes

AF:

0.0957

AC:

24048

AN:

251276

Hom.:

1910

AF XY:

0.0858

AC XY:

11658

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.0881

Gnomad EAS exome

AF:

0.0250

Gnomad SAS exome

AF:

0.0475

Gnomad FIN exome

AF:

0.0743

Gnomad NFE exome

AF:

0.0728

Gnomad OTH exome

AF:

0.0805

GnomAD4 exome

AF:

0.0793

AC:

115941

AN:

1461446

Hom.:

6340

Cov.:

AF XY:

0.0768

AC XY:

55833

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.346

Gnomad4 AMR exome

AF:

0.150

Gnomad4 ASJ exome

AF:

0.0857

Gnomad4 EAS exome

AF:

0.0234

Gnomad4 SAS exome

AF:

0.0469

Gnomad4 FIN exome

AF:

0.0768

Gnomad4 NFE exome

AF:

0.0727

Gnomad4 OTH exome

AF:

0.0871

GnomAD4 genome

AF:

0.148

AC:

22466

AN:

152056

Hom.:

2708

Cov.:

AF XY:

0.144

AC XY:

10691

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.331

Gnomad4 AMR

AF:

0.127

Gnomad4 ASJ

AF:

0.0890

Gnomad4 EAS

AF:

0.0250

Gnomad4 SAS

AF:

0.0475

Gnomad4 FIN

AF:

0.0705

Gnomad4 NFE

AF:

0.0745

Gnomad4 OTH

AF:

0.116

Alfa

AF:

0.0833

Hom.:

550

Bravo

AF:

0.162

TwinsUK

AF:

0.0666

AC:

247

ALSPAC

AF:

0.0765

AC:

295

ESP6500AA

AF:

0.321

AC:

1413

ESP6500EA

AF:

0.0745

AC:

641

ExAC

AF:

0.0992

AC:

12039

Asia WGS

AF:

0.0650

AC:

227

AN:

3478

EpiCase

AF:

0.0703

EpiControl

AF:

0.0641

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cone dystrophy with supernormal rod response

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.6

DANN

Benign

0.71

DEOGEN2

Benign

0.047

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.26

REVEL

Benign

0.20

Sift

Benign

0.98

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.017

MPC

0.017

ClinPred

0.0010

GERP RS

0.058

Varity_R

0.036

gMVP

0.47

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

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