dbSNP rs2236609: KCNE1:c.-50-129T>C (chr21-34449813-A-G) – ACMG Classification: Benign (-12 pts)

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.-50-129T>C variant causes a intron 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 7 hom., cov: 11)

Exomes 𝑓: 0.000047 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.35

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 21-34449813-A-G is Benign according to our data. Variant chr21-34449813-A-G is described in ClinVar as Benign. ClinVar VariationId is 671896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.-50-129T>C		intron_variant	Intron 3 of 3	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.-50-129T>C		intron_variant	Intron 3 of 3	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes

AF:

0.00493

AC:

385

AN:

78040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.0148

Gnomad AMR

AF:

0.00685

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00515

Gnomad SAS

AF:

0.00732

Gnomad FIN

AF:

0.00420

Gnomad MID

AF:

0.00581

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00282

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000467

AC:

AN:

321114

Hom.:

AF XY:

0.0000421

AC XY:

AN XY:

166290

show subpopulations

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

African (AFR)

AF:

0.000300

AC:

AN:

6656

American (AMR)

AF:

0.00

AC:

AN:

14268

Ashkenazi Jewish (ASJ)

AF:

0.000260

AC:

AN:

7682

East Asian (EAS)

AF:

0.00

AC:

AN:

13020

South Asian (SAS)

AF:

0.0000755

AC:

AN:

26484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1334

European-Non Finnish (NFE)

AF:

0.0000417

AC:

AN:

215932

Other (OTH)

AF:

0.00

AC:

AN:

16692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.296

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00498

AC:

389

AN:

78078

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

206

AN XY:

37862

show subpopulations

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

African (AFR)

AF:

0.0105

AC:

173

AN:

16530

American (AMR)

AF:

0.00683

AC:

AN:

8486

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

1736

East Asian (EAS)

AF:

0.00517

AC:

AN:

1936

South Asian (SAS)

AF:

0.00735

AC:

AN:

2178

European-Finnish (FIN)

AF:

0.00420

AC:

AN:

6662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

158

European-Non Finnish (NFE)

AF:

0.00221

AC:

AN:

38912

Other (OTH)

AF:

0.00279

AC:

AN:

1074

⚠️ 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: 0.255

Heterozygous variant carriers

147

196

245

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:

0.502

Hom.:

7697

Asia WGS

AF:

0.673

AC:

2341

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.0010

(source)

DANN

Benign

0.32

PhyloP100

-5.3

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over