NM_133497.4:c.-111C>T

Variant names:

• chr9-2717629-C-T
• rs188986938
• NM_133497.4:c.-111C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_133497.4(KCNV2):​c.-111C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,415,254 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: KCNV2 NM_133497.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.178
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00152 (231/152310) while in subpopulation NFE AF = 0.00196 (133/68022). AF 95% confidence interval is 0.00168. There are 2 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNV2	NM_133497.4	c.-111C>T		5_prime_UTR_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.-111C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_133497.4	ENSP00000371514.3
ENSG00000286670	ENST00000768783.1	n.113+28669G>A		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768784.1	n.156+14316G>A		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768785.1	n.156+14316G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00149 AC: 1888 AN: 1262944 Hom.: 2 Cov.: 18 AF XY: 0.00146 AC XY: 926 AN XY: 635734

African (AFR) AF: 0.000269 AC: 8 AN: 29742

American (AMR) AF: 0.000166 AC: 7 AN: 42272

Ashkenazi Jewish (ASJ) AF: 0.000614 AC: 15 AN: 24416

East Asian (EAS) AF: 0.00 AC: 0 AN: 38196

South Asian (SAS) AF: 0.00 AC: 0 AN: 80222

European-Finnish (FIN) AF: 0.0000610 AC: 3 AN: 49152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4496

European-Non Finnish (NFE) AF: 0.00190 AC: 1788 AN: 940744

Other (OTH) AF: 0.00125 AC: 67 AN: 53704

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74492

African (AFR) AF: 0.000505 AC: 21 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00158

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone dystrophy with supernormal rod response Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.76
PhyloP100		0.18
PromoterAI		-0.038	Neutral
Mutation Taster		=300/0	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: rs188986938; hg19: chr9-2717629;