rs199924386

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_012282.4(KCNE5):c.241T>C(p.Tyr81His) variant causes a missense change. The variant allele was found at a frequency of 0.000254 in 1,211,196 control chromosomes in the GnomAD database, including 2 homozygotes. There are 106 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 19 hem., cov: 25)

Exomes 𝑓: 0.00025 ( 2 hom. 87 hem. )

Consequence

KCNE5
NM_012282.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.73

Publications

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

ACSL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008243412).

BP6

Variant X-109624780-A-G is Benign according to our data. Variant chrX-109624780-A-G is described in ClinVar as Benign. ClinVar VariationId is 463280.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 35 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012282.4. 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
	KCNE5	NM_012282.4	MANE Select	c.241T>C	p.Tyr81His	missense	Exon 1 of 1	NP_036414.1	Q9UJ90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	ENST00000372101.3	TSL:6 MANE Select	c.241T>C	p.Tyr81His	missense	Exon 1 of 1	ENSP00000361173.2	Q9UJ90
	ACSL4	ENST00000439581.1	TSL:3	n.387-459T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

113280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00874

Gnomad SAS

AF:

0.000703

Gnomad FIN

AF:

0.000158

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000560

AC:

101

AN:

180382

AF XY:

0.000498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00705

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000448

GnomAD4 exome

AF:

0.000249

AC:

273

AN:

1097871

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

363345

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00775

AC:

234

AN:

30196

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

841927

Other (OTH)

AF:

0.000673

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000309

AC:

AN:

113325

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

AN XY:

35503

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31358

American (AMR)

AF:

0.00

AC:

AN:

10892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00877

AC:

AN:

3533

South Asian (SAS)

AF:

0.000705

AC:

AN:

2835

European-Finnish (FIN)

AF:

0.000158

AC:

AN:

6310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53295

Other (OTH)

AF:

0.00

AC:

AN:

1552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000510

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.000602

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome (1)

KCNE5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0082

MetaSVM

Uncertain

-0.23

PhyloP100

5.7

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.062

Vest4

0.27

MVP

0.19

MPC

1.4

ClinPred

0.15

GERP RS

3.5

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.90

gMVP

0.92

Mutation Taster

=89/11

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over