rs528809457

Variant names:

• chr9-2717595-T-C
• rs528809457
• NM_133497.4:c.-145T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_133497.4(KCNV2):​c.-145T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,030,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: KCNV2 NM_133497.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.627
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 9-2717595-T-C is Benign according to our data. Variant chr9-2717595-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 366400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000342 (52/152218) while in subpopulation EAS AF = 0.00971 (50/5148). AF 95% confidence interval is 0.00757. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNV2	NM_133497.4	c.-145T>C		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.-145T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_133497.4	ENSP00000371514.3
ENSG00000286670	ENST00000768783.1	n.113+28703A>G		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768784.1	n.156+14350A>G		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768785.1	n.156+14350A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00988

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000417 AC: 366 AN: 878350 Hom.: 0 Cov.: 12 AF XY: 0.000396 AC XY: 178 AN XY: 449372

African (AFR) AF: 0.00 AC: 0 AN: 21814

American (AMR) AF: 0.00 AC: 0 AN: 33122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19750

East Asian (EAS) AF: 0.0102 AC: 347 AN: 34038

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3112

European-Non Finnish (NFE) AF: 0.0000129 AC: 8 AN: 619208

Other (OTH) AF: 0.000246 AC: 10 AN: 40590

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00971 AC: 50 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000518

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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	-0.97
CADD	Benign	0.41
DANN	Benign	0.48
PhyloP100		-0.63
PromoterAI		0.016	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: rs528809457; hg19: chr9-2717595;