11-74457235-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005472.5(KCNE3):c.*17C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,611,564 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (27 hom.)
• Consequence: KCNE3 NM_005472.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.381

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-74457235-G-A is Benign according to our data. Variant chr11-74457235-G-A is described in ClinVar as [Benign]. Clinvar id is 137979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74457235-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1769/152248) while in subpopulation AFR AF= 0.0402 (1671/41538). AF 95% confidence interval is 0.0386. There are 31 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1764 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE3	NM_005472.5	c.*17C>T		3_prime_UTR_variant	3/3	ENST00000310128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE3	ENST00000310128.9	c.*17C>T		3_prime_UTR_variant	3/3	1	NM_005472.5	P1
KCNE3	ENST00000525550.1	c.*17C>T		3_prime_UTR_variant	2/2	1		P1
	ENST00000533008.1	n.155-26942G>A		intron_variant, non_coding_transcript_variant		3
KCNE3	ENST00000532569.5			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1764 AN: 152130 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00314 AC: 772 AN: 246152 Hom.: 5 AF XY: 0.00232 AC XY: 310 AN XY: 133630

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.000762

Gnomad FIN exome AF: 0.0000937

Gnomad NFE exome AF: 0.0000901

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00126 AC: 1833 AN: 1459316 Hom.: 27 Cov.: 30 AF XY: 0.00109 AC XY: 790 AN XY: 725814

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.00263

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000768

Gnomad4 FIN exome AF: 0.0000759

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.0116 AC: 1769 AN: 152248 Hom.: 31 Cov.: 32 AF XY: 0.0110 AC XY: 820 AN XY: 74450

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00947 Hom.: 5

Bravo AF: 0.0127

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2012	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.0
Dann	Benign	0.76

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: rs11822977; hg19: chr11-74168280;