11-74456329-CAAAAA-CAAAAAAAAA

Variant names:

• chr11-74456329-C-CAAAA
• rs60016728
• NM_005472.5:c.*919_*922dupTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005472.5(KCNE3):​c.*919_*922dupTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (342 hom., cov: 0)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: KCNE3 NM_005472.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.554
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.125 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.*919_*922dupTTTT		3_prime_UTR	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.*919_*922dupTTTT		3_prime_UTR	Exon 3 of 3	ENSP00000310557.4	Q9Y6H6
	KCNE3	ENST00000875764.1		c.*919_*922dupTTTT		3_prime_UTR	Exon 4 of 4	ENSP00000545823.1
	KCNE3	ENST00000929452.1		c.*919_*922dupTTTT		3_prime_UTR	Exon 4 of 4	ENSP00000599511.1

Frequencies

GnomAD3 genomes AF: 0.0703 AC: 8471 AN: 120426 Hom.: 343 Cov.: 0

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.0700

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0665

GnomAD4 exome AF: 0.172 AC: 10 AN: 58 Hom.: 0 Cov.: 0 AF XY: 0.214 AC XY: 9 AN XY: 42

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 10 AN: 50

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0703 AC: 8460 AN: 120414 Hom.: 342 Cov.: 0 AF XY: 0.0730 AC XY: 4158 AN XY: 56960

African (AFR) AF: 0.0395 AC: 1238 AN: 31364

American (AMR) AF: 0.0513 AC: 609 AN: 11870

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 208 AN: 3102

East Asian (EAS) AF: 0.0690 AC: 286 AN: 4146

South Asian (SAS) AF: 0.134 AC: 485 AN: 3608

European-Finnish (FIN) AF: 0.107 AC: 579 AN: 5422

Middle Eastern (MID) AF: 0.160 AC: 38 AN: 238

European-Non Finnish (NFE) AF: 0.0822 AC: 4785 AN: 58210

Other (OTH) AF: 0.0657 AC: 108 AN: 1644

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs60016728; hg19: chr11-74167374;