21-34369557-A-G

Variant names:

• chr21-34369557-A-G
• rs9984281
• NM_172201.2:c.-12-910A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172201.2(KCNE2):​c.-12-910A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 152,060 control chromosomes in the GnomAD database, including 2,382 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2382 hom., cov: 32)
• Consequence: KCNE2 NM_172201.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370
• Publications: 6 publications found

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]

KCNE2 Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000225555 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172201.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE2	NM_172201.2	MANE Select	c.-12-910A>G		intron	N/A	NP_751951.1
	LOC105372791	NR_188571.1		n.852+878T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE2	ENST00000290310.4	TSL:1 MANE Select	c.-12-910A>G		intron	N/A	ENSP00000290310.2
	KCNE2	ENST00000715813.1		c.-9-913A>G		intron	N/A	ENSP00000520524.1
	ENSG00000225555	ENST00000440403.2	TSL:3	n.854+878T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25754 AN: 151942 Hom.: 2376 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.0999

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.170 AC: 25785 AN: 152060 Hom.: 2382 Cov.: 32 AF XY: 0.169 AC XY: 12597 AN XY: 74330

African (AFR) AF: 0.207 AC: 8597 AN: 41442

American (AMR) AF: 0.157 AC: 2393 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1062 AN: 5168

South Asian (SAS) AF: 0.265 AC: 1274 AN: 4810

European-Finnish (FIN) AF: 0.0999 AC: 1057 AN: 10578

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10157 AN: 67996

Other (OTH) AF: 0.167 AC: 353 AN: 2112

Alfa AF: 0.166 Hom.: 1097

Bravo AF: 0.170

Asia WGS AF: 0.219 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.22
DANN	Benign	0.50
PhyloP100		-0.037
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9984281; hg19: chr21-35741856;