NM_005472.5:c.198T>G

Variant names:

• chr11-74457366-A-C
• rs2270676
• NM_005472.5:c.198T>G
• KCNE3 p.Phe66Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005472.5(KCNE3):​c.198T>G​(p.Phe66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F66F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNE3 NM_005472.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 0 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: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Brugada syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000254928 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17895639).

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>G	p.Phe66Leu	missense	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>G	p.Phe66Leu	missense	Exon 3 of 3	ENSP00000310557.4	Q9Y6H6
	KCNE3	ENST00000525550.1	TSL:1	c.198T>G	p.Phe66Leu	missense	Exon 2 of 2	ENSP00000433633.1	Q9Y6H6
	KCNE3	ENST00000875764.1		c.198T>G	p.Phe66Leu	missense	Exon 4 of 4	ENSP00000545823.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.43
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.070	N
REVEL	Uncertain	0.34
Sift	Benign	0.60	T
Sift4G	Benign	0.66	T
Varity_R		0.38
gMVP		0.69
Mutation Taster		=79/21	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2270676;

hg19: chr11-74168411;