rs2270676

Variant names:

• chr11-74457366-A-G
• rs2270676
• NM_005472.5:c.198T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-74457366-A-G
• chr11-74457366-A-C
• chr11-74457366-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005472.5(KCNE3):​c.198T>C​(p.Phe66Phe) 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:7
• Conservation: PhyloP100: 0.433
• Publications: 26 publications found

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]

KCNE3 Gene-Disease associations (from GenCC):

• Brugada syndrome 6

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Brugada syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000254928 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005472.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE3	NM_005472.5	MANE Select	c.198T>C	p.Phe66Phe	synonymous	Exon 3 of 3	NP_005463.1	Q9Y6H6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE3	ENST00000310128.9	TSL:1 MANE Select	c.198T>C	p.Phe66Phe	synonymous	Exon 3 of 3	ENSP00000310557.4	Q9Y6H6
	KCNE3	ENST00000525550.1	TSL:1	c.198T>C	p.Phe66Phe	synonymous	Exon 2 of 2	ENSP00000433633.1	Q9Y6H6
	KCNE3	ENST00000875764.1		c.198T>C	p.Phe66Phe	synonymous	Exon 4 of 4	ENSP00000545823.1

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

GnomAD2 exomes AF: 0.132 AC: 33053 AN: 251278 AF XY: 0.136

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 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

African (AFR) AF: 0.126 AC: 4204 AN: 33478

American (AMR) AF: 0.0887 AC: 3965 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2806 AN: 26132

East Asian (EAS) AF: 0.147 AC: 5818 AN: 39698

South Asian (SAS) AF: 0.208 AC: 17913 AN: 86258

European-Finnish (FIN) AF: 0.218 AC: 11654 AN: 53416

Middle Eastern (MID) AF: 0.121 AC: 699 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 120899 AN: 1111978

Other (OTH) AF: 0.125 AC: 7530 AN: 60392

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

African (AFR) AF: 0.123 AC: 5111 AN: 41558

American (AMR) AF: 0.0903 AC: 1383 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3472

East Asian (EAS) AF: 0.144 AC: 747 AN: 5186

South Asian (SAS) AF: 0.208 AC: 1004 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2409 AN: 10586

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7533 AN: 68000

Other (OTH) AF: 0.102 AC: 216 AN: 2112

Alfa AF: 0.112 Hom.: 4926

Bravo AF: 0.111

Asia WGS AF: 0.187 AC: 653 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Brugada syndrome 6 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		0.43
Mutation Taster		=98/2	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: rs2270676; hg19: chr11-74168411; COSMIC: COSV59552214; COSMIC: COSV59552214;