chr11-128839109-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153766.3(KCNJ1):c.*16G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,610,408 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 61 hom. )

Consequence

KCNJ1
NM_153766.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.28

Publications

2 publications found

Variant links:

Genes affected

KCNJ1 (HGNC:6255): (potassium inwardly rectifying channel subfamily J member 1) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. It is activated by internal ATP and probably plays an important role in potassium homeostasis. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNJ1 Gene-Disease associations (from GenCC):

Bartter disease type 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
antenatal Bartter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KCNJ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-128839109-C-T is Benign according to our data. Variant chr11-128839109-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 303568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00546 (831/152254) while in subpopulation NFE AF = 0.00838 (570/68008). AF 95% confidence interval is 0.00781. There are 6 homozygotes in GnomAd4. There are 404 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ1	NM_153766.3 link	c.*16G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000392666.6	NP_722450.1	P48048-2A0A024R3K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ1	ENST00000392666.6 link	c.*16G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_153766.3	ENSP00000376434.1		P48048-2

Frequencies

GnomAD3 genomes

AF:

0.00547

AC:

832

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00838

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00545

AC:

1360

AN:

249756

AF XY:

0.00543

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.00817

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00729

AC:

10624

AN:

1458154

Hom.:

Cov.:

AF XY:

0.00712

AC XY:

5166

AN XY:

725610

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33448

American (AMR)

AF:

0.00119

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000464

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.0158

AC:

814

AN:

51384

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00837

AC:

9290

AN:

1110528

Other (OTH)

AF:

0.00555

AC:

335

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

476

952

1427

1903

2379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00546

AC:

831

AN:

152254

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

404

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41558

American (AMR)

AF:

0.00183

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00838

AC:

570

AN:

68008

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00512

Hom.:

Bravo

AF:

0.00417

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bartter disease type 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.21

(source)

DANN

Benign

0.75

PhyloP100

-1.3

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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chr11-128839109-C-T

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