rs2270676

chr11-74457366-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005472.5(KCNE3):c.198T>C(p.Phe66=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,614,094 control chromosomes in the GnomAD database, including 12,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1316 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11444 hom.)
• Consequence: KCNE3 NM_005472.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.433

Genes affected

KCNE3 (HGNC:6243): (potassium voltage-gated channel subfamily E regulatory subunit 3) 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 type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 11-74457366-A-G is Benign according to our data. Variant chr11-74457366-A-G is described in ClinVar as [Benign]. Clinvar id is 259778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74457366-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.433 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE3	NM_005472.5	c.198T>C	p.Phe66=	synonymous_variant	3/3	ENST00000310128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE3	ENST00000310128.9	c.198T>C	p.Phe66=	synonymous_variant	3/3	1	NM_005472.5	P1
	ENST00000533008.1	n.155-26811A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18972 AN: 152132 Hom.: 1316 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.132 AC: 33053 AN: 251278 Hom.: 2535 AF XY: 0.136 AC XY: 18476 AN XY: 135816

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.120 AC: 175488 AN: 1461844 Hom.: 11444 Cov.: 32 AF XY: 0.123 AC XY: 89420 AN XY: 727224

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.0887

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.125 AC: 18976 AN: 152250 Hom.: 1316 Cov.: 32 AF XY: 0.132 AC XY: 9789 AN XY: 74440

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0903

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.102

Alfa AF: 0.109 Hom.: 2414

Bravo AF: 0.111

Asia WGS AF: 0.187 AC: 653 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Brugada syndrome 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 16374062) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	11
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs2270676; hg19: chr11-74168411; COSMIC: COSV59552214; COSMIC: COSV59552214;