Genetic Variant KCNE1:p.Thr10Thr (chr21-34449605-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000219.6(KCNE1):c.30G>A(p.Thr10Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T10T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 13)

Exomes 𝑓: 0.00021 ( 3 hom. )

Consequence

KCNE1
NM_000219.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.94

Publications

5 publications found

Variant links:

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 Gene-Disease associations (from GenCC):

long QT syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 21-34449605-C-T is Benign according to our data. Variant chr21-34449605-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.94 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNE1	NM_000219.6	MANE Select	c.30G>A	p.Thr10Thr	synonymous	Exon 4 of 4	NP_000210.2
KCNE1	NM_001127668.4		c.30G>A	p.Thr10Thr	synonymous	Exon 3 of 3	NP_001121140.1
KCNE1	NM_001127669.4		c.30G>A	p.Thr10Thr	synonymous	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.30G>A	p.Thr10Thr	synonymous	Exon 4 of 4	ENSP00000382226.2
KCNE1	ENST00000399289.7	TSL:1	c.30G>A	p.Thr10Thr	synonymous	Exon 3 of 3	ENSP00000382228.3
KCNE1	ENST00000416357.6	TSL:1	c.30G>A	p.Thr10Thr	synonymous	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

91292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000895

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00226

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000472

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000521

AC:

131

AN:

251232

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00582

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000213

AC:

175

AN:

822548

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

422140

show subpopulations

African (AFR)

AF:

0.000298

AC:

AN:

20106

American (AMR)

AF:

0.0000808

AC:

AN:

37106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19180

East Asian (EAS)

AF:

0.00243

AC:

AN:

33282

South Asian (SAS)

AF:

0.000187

AC:

AN:

64122

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

42514

Middle Eastern (MID)

AF:

0.000516

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.0000904

AC:

AN:

563862

Other (OTH)

AF:

0.000416

AC:

AN:

38502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000985

AC:

AN:

91360

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

44092

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000892

AC:

AN:

22430

American (AMR)

AF:

0.00

AC:

AN:

9828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2022

East Asian (EAS)

AF:

0.00189

AC:

AN:

2650

South Asian (SAS)

AF:

0.00

AC:

AN:

2710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000472

AC:

AN:

42384

Other (OTH)

AF:

0.00

AC:

AN:

1238

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00861026), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000117

Hom.:

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Jervell and Lange-Nielsen syndrome 2 (1)

KCNE1-related disorder (1)

Long QT syndrome (1)

Long QT syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.1

(source)

DANN

Benign

0.45

PhyloP100

-1.9

Mutation Taster

=100/0

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