21-34363867-G-A

Variant names:

• chr21-34363867-G-A
• rs13048252
• ENST00000440403.2:n.854+6568C>T

Variant summary

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

The ENST00000440403.2(ENSG00000225555):​n.854+6568C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,102 control chromosomes in the GnomAD database, including 22,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.52 (22151 hom., cov: 33)
• Consequence: ENSG00000225555 ENST00000440403.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

Genes affected

ENSG00000225555 (HGNC:):

KCNE2 (HGNC:6242): (potassium voltage-gated channel subfamily E regulatory subunit 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 channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-34363867-G-A is Benign according to our data. Variant chr21-34363867-G-A is described in ClinVar as [Benign]. Clinvar id is 683556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105372791	NR_188571.1	n.852+6568C>T		intron_variant	Intron 2 of 2
KCNE2	NM_172201.2	c.-297G>A		upstream_gene_variant		ENST00000290310.4	NP_751951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000225555	ENST00000440403.2	n.854+6568C>T		intron_variant	Intron 2 of 2	3
KCNE2	ENST00000290310.4	c.-297G>A		upstream_gene_variant		1	NM_172201.2	ENSP00000290310.2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78332 AN: 151984 Hom.: 22155 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.515 AC: 78334 AN: 152102 Hom.: 22151 Cov.: 33 AF XY: 0.523 AC XY: 38872 AN XY: 74344

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.758

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.542

Alfa AF: 0.591 Hom.: 54048

Bravo AF: 0.506

Asia WGS AF: 0.634 AC: 2209 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13048252; hg19: chr21-35736166;