rs41312842

chr9-2729475-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_133497.4(KCNV2):c.1386C>T(p.Asp462=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0703 in 1,613,786 control chromosomes in the GnomAD database, including 4,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (388 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4091 hom.)
• Consequence: KCNV2 NM_133497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.07

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]

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 9-2729475-C-T is Benign according to our data. Variant chr9-2729475-C-T is described in ClinVar as [Benign]. Clinvar id is 262359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2729475-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNV2	NM_133497.4	c.1386C>T	p.Asp462=	synonymous_variant	2/2	ENST00000382082.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNV2	ENST00000382082.4	c.1386C>T	p.Asp462=	synonymous_variant	2/2	1	NM_133497.4	P1
PUM3	ENST00000490444.2	c.*127-8943G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9606 AN: 152134 Hom.: 390 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0965

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.0703

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.0646

GnomAD3 exomes AF: 0.0745 AC: 18738 AN: 251370 Hom.: 897 AF XY: 0.0705 AC XY: 9584 AN XY: 135862

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0241

Gnomad SAS exome AF: 0.0466

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0724

Gnomad OTH exome AF: 0.0736

GnomAD4 exome AF: 0.0710 AC: 103778 AN: 1461534 Hom.: 4091 Cov.: 32 AF XY: 0.0697 AC XY: 50692 AN XY: 727080

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.0768

Gnomad4 NFE exome AF: 0.0726

Gnomad4 OTH exome AF: 0.0680

GnomAD4 genome AF: 0.0631 AC: 9604 AN: 152252 Hom.: 388 Cov.: 32 AF XY: 0.0620 AC XY: 4618 AN XY: 74448

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.0966

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.0241

Gnomad4 SAS AF: 0.0461

Gnomad4 FIN AF: 0.0703

Gnomad4 NFE AF: 0.0740

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.0733 Hom.: 242

Bravo AF: 0.0647

Asia WGS AF: 0.0360 AC: 127 AN: 3478

EpiCase AF: 0.0694

EpiControl AF: 0.0634

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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
BayesDel_noAF	Benign	-0.28
Cadd	Benign	9.6
Dann	Benign	0.82

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: rs41312842; hg19: chr9-2729475; COSMIC: COSV66057551;