NM_012282.4:c.55G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_012282.4(KCNE5):c.55G>T(p.Glu19*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,208,817 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 152 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 9 hem., cov: 25)

Exomes 𝑓: 0.00040 ( 0 hom. 143 hem. )

Consequence

KCNE5
NM_012282.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.02

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-109624966-C-A is Benign according to our data. Variant chrX-109624966-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581565.

BS2

High AC in GnomAd4 at 26 Unknown,AD 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.55G>T	p.Glu19*	stop_gained	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.55G>T	p.Glu19*	stop_gained	Exon 1 of 1	ENSP00000361173.2	Q9UJ90
	ACSL4	ENST00000439581.1	TSL:3	n.387-645G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

113070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000469

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000194

AC:

AN:

170214

AF XY:

0.000200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000206

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000401

AC:

439

AN:

1095747

Hom.:

Cov.:

AF XY:

0.000395

AC XY:

143

AN XY:

361613

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26363

American (AMR)

AF:

0.00

AC:

AN:

34974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19316

East Asian (EAS)

AF:

0.00

AC:

AN:

30085

South Asian (SAS)

AF:

0.00

AC:

AN:

53925

European-Finnish (FIN)

AF:

0.000175

AC:

AN:

39963

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.000496

AC:

417

AN:

841062

Other (OTH)

AF:

0.000283

AC:

AN:

45949

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

100

<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:

0.000230

AC:

AN:

113070

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

35220

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31154

American (AMR)

AF:

0.00

AC:

AN:

10900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000469

AC:

AN:

53265

Other (OTH)

AF:

0.00

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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:

0.0000869

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000456

AC:

ExAC

AF:

0.000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Brugada syndrome (1)

KCNE5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.49

PhyloP100

1.0

Vest4

0.12

GERP RS

2.2

PromoterAI

-0.076

Neutral

(source)

Mutation Taster

=168/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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