rs17003955

chrX-109624924-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012282.4(KCNE5):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,193,881 control chromosomes in the GnomAD database, including 8,816 homozygotes. There are 53,401 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (595 hom., 3183 hem., cov: 24)
  • Exomes 𝑓: 0.14 (8221 hom. 50218 hem.)
• Consequence: KCNE5 NM_012282.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.180

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001214087).
• BP6: Variant X-109624924-G-A is Benign according to our data. Variant chrX-109624924-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 381189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-109624924-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE5	NM_012282.4	c.97C>T	p.Pro33Ser	missense_variant	1/1	ENST00000372101.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE5	ENST00000372101.3	c.97C>T	p.Pro33Ser	missense_variant	1/1		NM_012282.4	P1
ACSL4	ENST00000439581.1	n.387-603C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0996 AC: 11224 AN: 112675 Hom.: 595 Cov.: 24 AF XY: 0.0913 AC XY: 3184 AN XY: 34861

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0694

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.0965

GnomAD3 exomes AF: 0.109 AC: 15962 AN: 145818 Hom.: 772 AF XY: 0.114 AC XY: 5276 AN XY: 46484

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0490

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.0568

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.143 AC: 155001 AN: 1081162 Hom.: 8221 Cov.: 32 AF XY: 0.143 AC XY: 50218 AN XY: 351456

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.000206

Gnomad4 SAS exome AF: 0.0599

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.0996 AC: 11223 AN: 112719 Hom.: 595 Cov.: 24 AF XY: 0.0912 AC XY: 3183 AN XY: 34917

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0663

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.00113

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.0953

Alfa AF: 0.144 Hom.: 4891

Bravo AF: 0.0924

ESP6500AA AF: 0.0167 AC: 63

ESP6500EA AF: 0.142 AC: 946

ExAC AF: 0.105 AC: 12265

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 10, 2023

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.3
Dann	Benign	0.76
DEOGEN2	Benign	0.060	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.072
Sift	Benign	0.41	T
Sift4G	Benign	0.082	T
Polyphen		0.0010	B
Vest4		0.018
MPC		0.38
ClinPred		0.0060	T
GERP RS		1.0
Varity_R		0.035
gMVP		0.62

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: rs17003955; hg19: chrX-108868153;