21-34370451-A-G

Variant names:

• chr21-34370451-A-G
• rs41314677
• NM_172201.2:c.-12-16A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172201.2(KCNE2):​c.-12-16A>G variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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]

ENSG00000225555 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KCNE2	NM_172201.2	c.-12-16A>G		intron_variant	Intron 1 of 1	ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1	n.836T>C		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1	n.836T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE2	ENST00000290310.4	c.-12-16A>G		intron_variant	Intron 1 of 1	1	NM_172201.2	ENSP00000290310.2

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

GnomAD2 exomes AF: 0.0365 AC: 9133 AN: 250390 AF XY: 0.0349

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 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

African (AFR) AF: 0.192 AC: 6430 AN: 33472

American (AMR) AF: 0.0238 AC: 1065 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 745 AN: 26136

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39698

South Asian (SAS) AF: 0.0398 AC: 3431 AN: 86252

European-Finnish (FIN) AF: 0.0146 AC: 781 AN: 53418

Middle Eastern (MID) AF: 0.0461 AC: 266 AN: 5768

European-Non Finnish (NFE) AF: 0.0336 AC: 37357 AN: 1111884

Other (OTH) AF: 0.0436 AC: 2632 AN: 60384

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

African (AFR) AF: 0.184 AC: 7642 AN: 41526

American (AMR) AF: 0.0396 AC: 606 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5194

South Asian (SAS) AF: 0.0390 AC: 188 AN: 4826

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2213 AN: 68020

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0484 Hom.: 135

Bravo AF: 0.0796

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.0
DANN	Benign	0.53
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

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Other links and lift over

dbSNP: rs41314677; hg19: chr21-35742750;