rs12720447

Positions:

• chr2-223052899-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_080671.4(KCNE4):​c.69C>T​(p.Ser23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,998 control chromosomes in the GnomAD database, including 549 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 0.036 (243 hom., cov: 33)
  • Exomes 𝑓: 0.011 (306 hom.)
• Consequence: KCNE4 NM_080671.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.832

Genes affected

KCNE4 (HGNC:6244): (potassium voltage-gated channel subfamily E regulatory subunit 4) 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 embryo and in adult uterus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=0.832 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE4	NM_080671.4	c.69C>T	p.Ser23=	synonymous_variant	2/2	ENST00000281830.4	NP_542402.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE4	ENST00000281830.4	c.69C>T	p.Ser23=	synonymous_variant	2/2	1	NM_080671.4	ENSP00000281830	P1
KCNE4	ENST00000488477.2	n.75+625C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5437 AN: 152206 Hom.: 243 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0194 AC: 4851 AN: 250504 Hom.: 134 AF XY: 0.0173 AC XY: 2345 AN XY: 135638

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0361

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00941

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0110 AC: 16141 AN: 1461674 Hom.: 306 Cov.: 31 AF XY: 0.0111 AC XY: 8049 AN XY: 727154

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00897

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.00353

Gnomad4 NFE exome AF: 0.00642

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0358 AC: 5448 AN: 152324 Hom.: 243 Cov.: 33 AF XY: 0.0344 AC XY: 2563 AN XY: 74470

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0101

Gnomad4 SAS AF: 0.0309

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00579

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0184 Hom.: 60

Bravo AF: 0.0410

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00664

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.81

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: rs12720447; hg19: chr2-223917617;