Genetic Variant NM_080671.4:c.435T>G (chr2-223053265-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_080671.4(KCNE4):c.435T>G(p.Asp145Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,613,456 control chromosomes in the GnomAD database, including 401,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D145N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.66 ( 33910 hom., cov: 33)

Exomes 𝑓: 0.71 ( 367958 hom. )

Consequence

KCNE4
NM_080671.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.76

Publications

63 publications found

Variant links:

Genes affected

KCNE4 (HGNC:6244): (potassium voltage-gated channel subfamily E regulatory subunit 4) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the embryo and in adult uterus. [provided by RefSeq, Jul 2008]

KCNE4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.0552725E-7).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE4	NM_080671.4 link	c.435T>G	p.Asp145Glu	missense_variant	Exon 2 of 2	ENST00000281830.4	NP_542402.4	Q8WWG9A5H1P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE4	ENST00000281830.4 link	c.435T>G	p.Asp145Glu	missense_variant	Exon 2 of 2	1	NM_080671.4	ENSP00000281830.5		Q8WWG9
KCNE4	ENST00000488477.2 link	n.75+991T>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100279

AN:

151860

Hom.:

33882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.520

Gnomad AMI

AF:

0.642

Gnomad AMR

AF:

0.719

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.699

Gnomad SAS

AF:

0.811

Gnomad FIN

AF:

0.789

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.705

Gnomad OTH

AF:

0.648

GnomAD2 exomes

AF:

0.710

AC:

177198

AN:

249704

AF XY:

0.713

show subpopulations

Gnomad AFR exome

AF:

0.520

Gnomad AMR exome

AF:

0.774

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.697

Gnomad FIN exome

AF:

0.785

Gnomad NFE exome

AF:

0.698

Gnomad OTH exome

AF:

0.683

GnomAD4 exome

AF:

0.708

AC:

1034222

AN:

1461476

Hom.:

367958

Cov.:

AF XY:

0.710

AC XY:

516190

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.523

AC:

17481

AN:

33404

American (AMR)

AF:

0.765

AC:

34221

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

14465

AN:

26136

East Asian (EAS)

AF:

0.668

AC:

26534

AN:

39696

South Asian (SAS)

AF:

0.794

AC:

68519

AN:

86246

European-Finnish (FIN)

AF:

0.784

AC:

41751

AN:

53234

Middle Eastern (MID)

AF:

0.537

AC:

3096

AN:

5768

European-Non Finnish (NFE)

AF:

0.707

AC:

786655

AN:

1111888

Other (OTH)

AF:

0.687

AC:

41500

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17767

35534

53301

71068

88835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19782

39564

59346

79128

98910

<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:

0.660

AC:

100357

AN:

151980

Hom.:

33910

Cov.:

AF XY:

0.669

AC XY:

49684

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.520

AC:

21533

AN:

41386

American (AMR)

AF:

0.719

AC:

11002

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

1965

AN:

3472

East Asian (EAS)

AF:

0.698

AC:

3580

AN:

5132

South Asian (SAS)

AF:

0.810

AC:

3899

AN:

4816

European-Finnish (FIN)

AF:

0.789

AC:

8365

AN:

10602

Middle Eastern (MID)

AF:

0.517

AC:

151

AN:

292

European-Non Finnish (NFE)

AF:

0.705

AC:

47908

AN:

67966

Other (OTH)

AF:

0.650

AC:

1371

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1720

3440

5160

6880

8600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.678

Hom.:

73946

Bravo

AF:

0.644

TwinsUK

AF:

0.706

AC:

2616

ALSPAC

AF:

0.716

AC:

2758

ESP6500AA

AF:

0.534

AC:

2352

ESP6500EA

AF:

0.700

AC:

6020

ExAC

AF:

0.702

AC:

85167

Asia WGS

AF:

0.727

AC:

2531

AN:

3478

EpiCase

AF:

0.672

EpiControl

AF:

0.674

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.022

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.071

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.56

MetaRNN

Benign

6.1e-7

MetaSVM

Benign

-0.96

PhyloP100

-1.8

PrimateAI

Benign

0.40

REVEL

Benign

0.14

Sift4G

Benign

0.71

Vest4

0.029

ClinPred

0.016

GERP RS

-11

Varity_R

0.067

gMVP

0.23

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over