21-34370451-A-G

Variant summary

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

The NM_172201.2(KCNE2):c.-12-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,614,000 control chromosomes in the GnomAD database, including 2,254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (777 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1477 hom.)
• Consequence: KCNE2 NM_172201.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.146

Genes affected

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-34370451-A-G is Benign according to our data. Variant chr21-34370451-A-G is described in ClinVar as [Benign]. Clinvar id is 262799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-34370451-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE2	NM_172201.2	c.-12-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000290310.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE2	ENST00000290310.4	c.-12-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_172201.2	P1
	ENST00000440403.2	n.838T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11101 AN: 152148 Hom.: 768 Cov.: 33

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0365 AC: 9133 AN: 250390 Hom.: 403 AF XY: 0.0349 AC XY: 4739 AN XY: 135672

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.000924

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0361 AC: 52789 AN: 1461734 Hom.: 1477 Cov.: 31 AF XY: 0.0360 AC XY: 26171 AN XY: 727182

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.0285

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0398

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0336

Gnomad4 OTH exome AF: 0.0436

GnomAD4 genome AF: 0.0731 AC: 11132 AN: 152266 Hom.: 777 Cov.: 33 AF XY: 0.0698 AC XY: 5200 AN XY: 74452

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.0396

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0390

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0472 Hom.: 69

Bravo AF: 0.0796

Asia WGS AF: 0.0380 AC: 130 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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.0
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41314677; hg19: chr21-35742750;