2-223052864-C-A

Variant names:

• chr2-223052864-C-A
• NM_080671.4:c.34C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080671.4(KCNE4):​c.34C>A​(p.Pro12Thr) 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. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNE4 NM_080671.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0626173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE4	NM_080671.4	c.34C>A	p.Pro12Thr	missense_variant	Exon 2 of 2	ENST00000281830.4	NP_542402.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE4	ENST00000281830.4	c.34C>A	p.Pro12Thr	missense_variant	Exon 2 of 2	1	NM_080671.4	ENSP00000281830.5
KCNE4	ENST00000488477.2	n.75+590C>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>A (p.P12T) alteration is located in exon 2 (coding exon 1) of the KCNE4 gene. This alteration results from a C to A substitution at nucleotide position 34, causing the proline (P) at amino acid position 12 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.26	T
REVEL	Benign	0.076
Sift4G	Benign	0.43	T
Vest4		0.080
MVP		0.043
ClinPred		0.10	T
GERP RS		2.9
Varity_R		0.15
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-223917582;