Genetic Variant KCNE4:p.Gly27Gly (chr2-223052911-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_080671.4(KCNE4):c.81C>T(p.Gly27Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,866 control chromosomes in the GnomAD database, including 407,892 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.71 ( 38623 hom., cov: 34)

Exomes 𝑓: 0.71 ( 369269 hom. )

Consequence

KCNE4
NM_080671.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.792

Publications

17 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP7

Synonymous conserved (PhyloP=0.792 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE4	NM_080671.4 link	c.81C>T	p.Gly27Gly	synonymous_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.81C>T	p.Gly27Gly	synonymous_variant	Exon 2 of 2	1	NM_080671.4	ENSP00000281830.5		Q8WWG9
KCNE4	ENST00000488477.2 link	n.75+637C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.711

AC:

108083

AN:

152092

Hom.:

38596

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.571

Gnomad EAS

AF:

0.654

Gnomad SAS

AF:

0.818

Gnomad FIN

AF:

0.788

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.703

Gnomad OTH

AF:

0.684

GnomAD2 exomes

AF:

0.716

AC:

179684

AN:

250882

AF XY:

0.718

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.559

Gnomad EAS exome

AF:

0.652

Gnomad FIN exome

AF:

0.785

Gnomad NFE exome

AF:

0.697

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.709

AC:

1036894

AN:

1461656

Hom.:

369269

Cov.:

AF XY:

0.711

AC XY:

517300

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.716

AC:

23983

AN:

33476

American (AMR)

AF:

0.745

AC:

33320

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.558

AC:

14588

AN:

26126

East Asian (EAS)

AF:

0.618

AC:

24551

AN:

39696

South Asian (SAS)

AF:

0.801

AC:

69076

AN:

86258

European-Finnish (FIN)

AF:

0.784

AC:

41796

AN:

53320

Middle Eastern (MID)

AF:

0.549

AC:

3163

AN:

5766

European-Non Finnish (NFE)

AF:

0.705

AC:

784284

AN:

1111908

Other (OTH)

AF:

0.698

AC:

42133

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

19695

39390

59084

78779

98474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19786

39572

59358

79144

98930

<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:

0.711

AC:

108160

AN:

152210

Hom.:

38623

Cov.:

AF XY:

0.718

AC XY:

53410

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.709

AC:

29452

AN:

41542

American (AMR)

AF:

0.723

AC:

11070

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.571

AC:

1982

AN:

3470

East Asian (EAS)

AF:

0.653

AC:

3363

AN:

5148

South Asian (SAS)

AF:

0.816

AC:

3942

AN:

4828

European-Finnish (FIN)

AF:

0.788

AC:

8349

AN:

10596

Middle Eastern (MID)

AF:

0.541

AC:

159

AN:

294

European-Non Finnish (NFE)

AF:

0.703

AC:

47807

AN:

68004

Other (OTH)

AF:

0.685

AC:

1449

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1665

3329

4994

6658

8323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.694

Hom.:

72335

Bravo

AF:

0.700

Asia WGS

AF:

0.721

AC:

2511

AN:

3478

EpiCase

AF:

0.671

EpiControl

AF:

0.672

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.5

(source)

DANN

Benign

0.65

PhyloP100

0.79

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