chr21-34370500-A-G

Variant names:

• chr21-34370500-A-G
• rs2234916
• NM_172201.2:c.22A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_172201.2(KCNE2):​c.22A>G​(p.Thr8Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,180 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (38 hom.)
• Consequence: KCNE2 NM_172201.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 7.93

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031698614).
• BP6: Variant 21-34370500-A-G is Benign according to our data. Variant chr21-34370500-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67615.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=2, Benign=6}. Variant chr21-34370500-A-G is described in Lovd as [Benign]. Variant chr21-34370500-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE2	NM_172201.2	c.22A>G	p.Thr8Ala	missense_variant	Exon 2 of 2	ENST00000290310.4	NP_751951.1
LOC105372791	NR_188571.1	n.787T>C		non_coding_transcript_exon_variant	Exon 2 of 3
LOC105372791	NR_188572.1	n.787T>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.22A>G	p.Thr8Ala	missense_variant	Exon 2 of 2	1	NM_172201.2	ENSP00000290310.2

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152174 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00372 AC: 935 AN: 251318 AF XY: 0.00384

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00602

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00563 AC: 8235 AN: 1461888 Hom.: 38 Cov.: 31 AF XY: 0.00549 AC XY: 3995 AN XY: 727246

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00311 AC: 139 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86258

European-Finnish (FIN) AF: 0.00423 AC: 226 AN: 53420

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.00659 AC: 7332 AN: 1112006

Other (OTH) AF: 0.00573 AC: 346 AN: 60396

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152292 Hom.: 4 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74456

African (AFR) AF: 0.000938 AC: 39 AN: 41572

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68012

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00544 Hom.: 8

Bravo AF: 0.00367

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00380 AC: 461

EpiCase AF: 0.00583

EpiControl AF: 0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2 Other:1

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNE2: BS2 -

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:10984545;PMID:11468227;PMID:12402336;PMID:14661677;PMID:14760488;PMID:15599693;PMID:17161064;PMID:17210839). -

Long QT syndrome 6 Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome Benign:2

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PP3, BS1, BS2 -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 08, 2011

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. -

Cardiovascular phenotype Benign:1

Jun 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Long QT syndrome, drug-associated Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.97
MPC		0.52
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.53
gMVP		0.98
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2234916; hg19: chr21-35742799; COSMIC: COSV51710582; COSMIC: COSV51710582;