rs1554628460

Variant names:

• chr9-2717843-C-CCCGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGT
• rs1554628460
• NM_133497.4:c.107_291dupGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGTCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_133497.4(KCNV2):​c.107_291dupGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGTCC​(p.Thr98ValfsTer64) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T98T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNV2 NM_133497.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.572
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-2717843-C-CCCGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGT is Pathogenic according to our data. Variant chr9-2717843-C-CCCGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438243.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNV2	NM_133497.4	c.107_291dupGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGTCC	p.Thr98ValfsTer64	frameshift_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.107_291dupGTTCCGGCTCCCAGGCCAGCATCCACGGCTGGACAGAGGGCAACTATAACTACTACATCGAGGAAGACGAAGACGGCGAGGAGGAGGACCAGTGGAAGGACGACCTGGCAGAAGAGGACCAGCAGGCAGGGGAGGTCACCACCGCCAAGCCCGAGGGCCCCAGCGACCCTCCGGCCCTGCTGTCC	p.Thr98ValfsTer64	frameshift_variant	Exon 1 of 2	1	NM_133497.4	ENSP00000371514.3
ENSG00000286670	ENST00000768783.1	n.113+28270_113+28454dupACAGCAGGGCCGGAGGGTCGCTGGGGCCCTCGGGCTTGGCGGTGGTGACCTCCCCTGCCTGCTGGTCCTCTTCTGCCAGGTCGTCCTTCCACTGGTCCTCCTCCTCGCCGTCTTCGTCTTCCTCGATGTAGTAGTTATAGTTGCCCTCTGTCCAGCCGTGGATGCTGGCCTGGGAGCCGGAACGG		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768784.1	n.156+13917_156+14101dupACAGCAGGGCCGGAGGGTCGCTGGGGCCCTCGGGCTTGGCGGTGGTGACCTCCCCTGCCTGCTGGTCCTCTTCTGCCAGGTCGTCCTTCCACTGGTCCTCCTCCTCGCCGTCTTCGTCTTCCTCGATGTAGTAGTTATAGTTGCCCTCTGTCCAGCCGTGGATGCTGGCCTGGGAGCCGGAACGG		intron_variant	Intron 1 of 3
ENSG00000286670	ENST00000768785.1	n.156+13917_156+14101dupACAGCAGGGCCGGAGGGTCGCTGGGGCCCTCGGGCTTGGCGGTGGTGACCTCCCCTGCCTGCTGGTCCTCTTCTGCCAGGTCGTCCTTCCACTGGTCCTCCTCCTCGCCGTCTTCGTCTTCCTCGATGTAGTAGTTATAGTTGCCCTCTGTCCAGCCGTGGATGCTGGCCTGGGAGCCGGAACGG		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554628460; hg19: chr9-2717843;