rs17003955

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/19 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.180

Publications

16 publications found

Variant links:

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]

KCNE5 links:

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]

ACSL4 Gene-Disease associations (from GenCC):

non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Illumina, Orphanet
intellectual disability, X-linked 63
Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACSL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 381189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
KCNE5	NM_012282.4 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 1	ENST00000372101.3	NP_036414.1	Q9UJ90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE5	ENST00000372101.3 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 1	6	NM_012282.4	ENSP00000361173.2		Q9UJ90
ACSL4	ENST00000439581.1 link	n.387-603C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0996

AC:

11224

AN:

112675

Hom.:

595

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.109

AC:

15962

AN:

145818

AF XY:

0.114

show subpopulations

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 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.:

AF XY:

0.143

AC XY:

50218

AN XY:

351456

show subpopulations

African (AFR)

AF:

0.0174

AC:

451

AN:

25992

American (AMR)

AF:

0.0517

AC:

1717

AN:

33223

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

3837

AN:

19169

East Asian (EAS)

AF:

0.000206

AC:

AN:

29146

South Asian (SAS)

AF:

0.0599

AC:

3104

AN:

51803

European-Finnish (FIN)

AF:

0.121

AC:

4456

AN:

36919

Middle Eastern (MID)

AF:

0.136

AC:

529

AN:

3888

European-Non Finnish (NFE)

AF:

0.161

AC:

134804

AN:

835550

Other (OTH)

AF:

0.134

AC:

6097

AN:

45472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

5830

11659

17489

23318

29148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4848

9696

14544

19392

24240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0996

AC:

11223

AN:

112719

Hom.:

595

Cov.:

AF XY:

0.0912

AC XY:

3183

AN XY:

34917

show subpopulations

African (AFR)

AF:

0.0200

AC:

625

AN:

31277

American (AMR)

AF:

0.0663

AC:

720

AN:

10865

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

548

AN:

2643

East Asian (EAS)

AF:

0.00113

AC:

AN:

3531

South Asian (SAS)

AF:

0.0495

AC:

138

AN:

2789

European-Finnish (FIN)

AF:

0.118

AC:

735

AN:

6205

Middle Eastern (MID)

AF:

0.177

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.155

AC:

8221

AN:

52974

Other (OTH)

AF:

0.0953

AC:

147

AN:

1543

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

336

672

1009

1345

1681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.132

Hom.:

4963

Bravo

AF:

0.0924

ESP6500AA

AF:

0.0167

AC:

ESP6500EA

AF:

0.142

AC:

946

ExAC

AF:

0.105

AC:

12265

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 10, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.3

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.060

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.1

PhyloP100

0.18

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.80

REVEL

Benign

0.072

Sift

Benign

0.41

Sift4G

Benign

0.082

Polyphen

0.0010

Vest4

0.018

MPC

0.38

ClinPred

0.0060

GERP RS

1.0

PromoterAI

0.013

Neutral

(source)

Varity_R

0.035

gMVP

0.62

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over