9-2718498-A-G

Variant names:

• chr9-2718498-A-G
• rs10967709
• NM_133497.4:c.759A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133497.4(KCNV2):​c.759A>G​(p.Pro253Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,610,338 control chromosomes in the GnomAD database, including 8,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (852 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8130 hom.)
• Consequence: KCNV2 NM_133497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.31
• Publications: 9 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 9-2718498-A-G is Benign according to our data. Variant chr9-2718498-A-G is described in ClinVar as Benign. ClinVar VariationId is 96361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133497.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNV2	NM_133497.4	MANE Select	c.759A>G	p.Pro253Pro	synonymous	Exon 1 of 2	NP_598004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNV2	ENST00000382082.4	TSL:1 MANE Select	c.759A>G	p.Pro253Pro	synonymous	Exon 1 of 2	ENSP00000371514.3
	ENSG00000286670	ENST00000768783.1		n.113+27800T>C		intron	N/A
	ENSG00000286670	ENST00000768784.1		n.156+13447T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15281 AN: 152068 Hom.: 853 Cov.: 33

Gnomad AFR AF: 0.0851

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0490

Gnomad FIN AF: 0.0797

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.102 AC: 24074 AN: 236654 AF XY: 0.0970

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.0807

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.102 AC: 148151 AN: 1458152 Hom.: 8130 Cov.: 80 AF XY: 0.0996 AC XY: 72233 AN XY: 725228

African (AFR) AF: 0.0819 AC: 2741 AN: 33450

American (AMR) AF: 0.168 AC: 7456 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4501 AN: 26046

East Asian (EAS) AF: 0.0186 AC: 737 AN: 39598

South Asian (SAS) AF: 0.0472 AC: 4054 AN: 85902

European-Finnish (FIN) AF: 0.0861 AC: 4474 AN: 51970

Middle Eastern (MID) AF: 0.0961 AC: 553 AN: 5754

European-Non Finnish (NFE) AF: 0.106 AC: 117558 AN: 1110900

Other (OTH) AF: 0.101 AC: 6077 AN: 60232

GnomAD4 genome AF: 0.100 AC: 15283 AN: 152186 Hom.: 852 Cov.: 33 AF XY: 0.0992 AC XY: 7381 AN XY: 74428

African (AFR) AF: 0.0850 AC: 3531 AN: 41534

American (AMR) AF: 0.146 AC: 2228 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3470

East Asian (EAS) AF: 0.0251 AC: 129 AN: 5136

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4830

European-Finnish (FIN) AF: 0.0797 AC: 846 AN: 10616

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7350 AN: 67990

Other (OTH) AF: 0.102 AC: 215 AN: 2114

Alfa AF: 0.0974 Hom.: 321

Bravo AF: 0.105

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 20, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone dystrophy with supernormal rod response Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.2
DANN	Benign	0.48
PhyloP100		-1.3
Mutation Taster		=95/5	polymorphism (auto)

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: rs10967709; hg19: chr9-2718498;