chr21-34449523-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000219.6(KCNE1):c.112A>G(p.Ser38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S38R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 12)

Exomes 𝑓: 0.00069 ( 289 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: -1.04

Publications

150 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.5166795E-5).

BP6

Variant 21-34449523-T-C is Benign according to our data. Variant chr21-34449523-T-C is described in ClinVar as Benign. ClinVar VariationId is 132651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.112A>G	p.Ser38Gly	missense	Exon 4 of 4	NP_000210.2
KCNE1	NM_001127668.4		c.112A>G	p.Ser38Gly	missense	Exon 3 of 3	NP_001121140.1
KCNE1	NM_001127669.4		c.112A>G	p.Ser38Gly	missense	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.112A>G	p.Ser38Gly	missense	Exon 4 of 4	ENSP00000382226.2
KCNE1	ENST00000399289.7	TSL:1	c.112A>G	p.Ser38Gly	missense	Exon 3 of 3	ENSP00000382228.3
KCNE1	ENST00000416357.6	TSL:1	c.112A>G	p.Ser38Gly	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes

AF:

0.000203

AC:

AN:

74030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000618

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000948

Gnomad FIN

AF:

0.000160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000224

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.643

AC:

161537

AN:

251288

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.712

Gnomad AMR exome

AF:

0.593

Gnomad ASJ exome

AF:

0.699

Gnomad EAS exome

AF:

0.711

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.643

Gnomad OTH exome

AF:

0.639

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000692

AC:

584

AN:

843966

Hom.:

289

Cov.:

AF XY:

0.000727

AC XY:

305

AN XY:

419698

show subpopulations

African (AFR)

AF:

0.00208

AC:

AN:

16350

American (AMR)

AF:

0.000629

AC:

AN:

28614

Ashkenazi Jewish (ASJ)

AF:

0.000872

AC:

AN:

13762

East Asian (EAS)

AF:

0.00619

AC:

114

AN:

18428

South Asian (SAS)

AF:

0.000369

AC:

AN:

48814

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

35312

Middle Eastern (MID)

AF:

0.000585

AC:

AN:

3418

European-Non Finnish (NFE)

AF:

0.000479

AC:

309

AN:

645036

Other (OTH)

AF:

0.00108

AC:

AN:

34232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000203

AC:

AN:

74064

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

AN XY:

36188

show subpopulations

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

African (AFR)

AF:

0.000179

AC:

AN:

16798

American (AMR)

AF:

0.00

AC:

AN:

8192

Ashkenazi Jewish (ASJ)

AF:

0.000618

AC:

AN:

1618

East Asian (EAS)

AF:

0.00

AC:

AN:

2026

South Asian (SAS)

AF:

0.000951

AC:

AN:

2102

European-Finnish (FIN)

AF:

0.000160

AC:

AN:

6232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

35632

Other (OTH)

AF:

0.00

AC:

AN:

994

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

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:

0.644

Hom.:

131449

TwinsUK

AF:

0.641

AC:

2375

ALSPAC

AF:

0.636

AC:

2453

ESP6500AA

AF:

0.711

AC:

3132

ESP6500EA

AF:

0.637

AC:

5477

ExAC

AF:

0.647

AC:

78583

Asia WGS

AF:

0.710

AC:

2465

AN:

3478

EpiCase

AF:

0.632

EpiControl

AF:

0.630

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Jervell and Lange-Nielsen syndrome 2 (2)

Long QT syndrome 5 (2)

not provided (3)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Long QT syndrome (1)

Noise induced hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

2.4

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.40

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.084

MetaRNN

Benign

0.000035

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

PhyloP100

-1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.43

REVEL

Benign

0.28

Sift

Benign

0.40

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.019

MPC

0.068

ClinPred

0.015

GERP RS

0.18

Varity_R

0.038

gMVP

0.39

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over