9-2717759-G-C

Variant names:

• chr9-2717759-G-C
• rs370186140
• NM_133497.4:c.20G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133497.4(KCNV2):​c.20G>C​(p.Arg7Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R7K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNV2 NM_133497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• cone dystrophy with supernormal rod response

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000286670 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNV2	NM_133497.4	c.20G>C	p.Arg7Thr	missense_variant	Exon 1 of 2	ENST00000382082.4	NP_598004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNV2	ENST00000382082.4	c.20G>C	p.Arg7Thr	missense_variant	Exon 1 of 2	1	NM_133497.4	ENSP00000371514.3
ENSG00000286670	ENST00000768783.1	n.113+28539C>G		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768784.1	n.156+14186C>G		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768785.1	n.156+14186C>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 7 of the KCNV2 protein (p.Arg7Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNV2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1002351). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.87	P
Vest4		0.64
MutPred		0.19		Gain of phosphorylation at R7 (P = 0.0154);
MVP		0.98
MPC		0.10
ClinPred		0.88	D
GERP RS		4.9
PromoterAI		0.015	Neutral
Varity_R		0.26
gMVP		0.63
Mutation Taster		=87/13	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: rs370186140; hg19: chr9-2717759;