X-109624675-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012282.4(KCNE5):c.346G>T(p.Ala116Ser) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: KCNE5 NM_012282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

Genes affected

KCNE5 (HGNC:6241): (potassium voltage-gated channel subfamily E regulatory subunit 5) This gene encodes a member of a family of single pass transmembrane domain proteins that function as ancillary subunits to voltage-gated potassium channels. Members of this family affect diverse processes in potassium channel regulation, including ion selectivity, voltage dependence, and anterograde recycling from the plasma membrane. Variants of this gene are associated with idiopathic ventricular fibrillation and Brugada syndrome. [provided by RefSeq, Nov 2016]

ACSL4 (HGNC:3571): (acyl-CoA synthetase long chain family member 4) The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10657042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE5	NM_012282.4	c.346G>T	p.Ala116Ser	missense_variant	1/1	ENST00000372101.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE5	ENST00000372101.3	c.346G>T	p.Ala116Ser	missense_variant	1/1		NM_012282.4	P1
ACSL4	ENST00000439581.1	n.387-354G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1059564 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 343852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The p.A116S variant (also known as c.346G>T), located in coding exon 1 of the KCNE5 gene, results from a G to T substitution at nucleotide position 346. The alanine at codon 116 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	9.8
Dann	Benign	0.92
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.043
Sift	Benign	0.16	T
Sift4G	Benign	0.30	T
Polyphen		0.069	B
Vest4		0.15
MutPred		0.13		Gain of glycosylation at A116 (P = 0.0024);
MVP		0.067
MPC		0.43
ClinPred		0.10	T
GERP RS		2.6
Varity_R		0.080
gMVP		0.30

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: rs764993726; hg19: chrX-108867904;