rs41306094

Positions:

• chr9-2729733-T-C
• chr9-2729733-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133497.4(KCNV2):​c.*6T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 1,612,442 control chromosomes in the GnomAD database, including 5,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (963 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4634 hom.)
• Consequence: KCNV2 NM_133497.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.423

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-2729733-T-C is Benign according to our data. Variant chr9-2729733-T-C is described in ClinVar as [Benign]. Clinvar id is 262358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2729733-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNV2	NM_133497.4	c.*6T>C		3_prime_UTR_variant	2/2	ENST00000382082.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNV2	ENST00000382082.4	c.*6T>C		3_prime_UTR_variant	2/2	1	NM_133497.4	P1
PUM3	ENST00000490444.2	c.*127-9201A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15197 AN: 152074 Hom.: 950 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0745

Gnomad OTH AF: 0.0891

GnomAD3 exomes AF: 0.0842 AC: 21104 AN: 250632 Hom.: 1148 AF XY: 0.0779 AC XY: 10557 AN XY: 135528

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0242

Gnomad SAS exome AF: 0.0480

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0728

Gnomad OTH exome AF: 0.0786

GnomAD4 exome AF: 0.0745 AC: 108850 AN: 1460250 Hom.: 4634 Cov.: 31 AF XY: 0.0728 AC XY: 52896 AN XY: 726580

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.0469

Gnomad4 FIN exome AF: 0.0768

Gnomad4 NFE exome AF: 0.0724

Gnomad4 OTH exome AF: 0.0771

GnomAD4 genome AF: 0.100 AC: 15245 AN: 152192 Hom.: 963 Cov.: 32 AF XY: 0.0987 AC XY: 7345 AN XY: 74398

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.0242

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.0704

Gnomad4 NFE AF: 0.0745

Gnomad4 OTH AF: 0.0867

Alfa AF: 0.0813 Hom.: 439

Bravo AF: 0.107

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

-

- -

Cone dystrophy with supernormal rod response Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.84
CADD	Benign	0.97
DANN	Benign	0.56

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: rs41306094; hg19: chr9-2729733;