rs41302407

Positions:

chr11-128840045-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_153766.3(KCNJ1):c.199A>G(p.Thr67Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,150 control chromosomes in the GnomAD database, including 561 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 68 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 493 hom. )

Consequence

KCNJ1
NM_153766.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.41

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 links:

KCNJ1 (HGNC:):

KCNJ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity KCNJ1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_153766.3

BP4

Computational evidence support a benign effect (MetaRNN=0.001817733).

BP6

Variant 11-128840045-T-C is Benign according to our data. Variant chr11-128840045-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 235236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ1	NM_153766.3 linkuse as main transcript	c.199A>G	p.Thr67Ala	missense_variant	3/3	ENST00000392666.6	NP_722450.1	P48048-2A0A024R3K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ1	ENST00000392666.6 linkuse as main transcript	c.199A>G	p.Thr67Ala	missense_variant	3/3	1	NM_153766.3	ENSP00000376434.1		P48048-2

Frequencies

GnomAD3 genomes

AF:

0.00907

AC:

1380

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0739

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0113

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00547

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0221

AC:

5549

AN:

251256

Hom.:

420

AF XY:

0.0165

AC XY:

2241

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.000581

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.00519

AC:

7592

AN:

1461852

Hom.:

493

Cov.:

AF XY:

0.00445

AC XY:

3239

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.0159

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.00367

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.00444

GnomAD4 genome

AF:

0.00910

AC:

1386

AN:

152298

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

806

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.0742

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0114

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00547

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.0153

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.0169

AC:

2057

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

KCNJ1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Antenatal Bartter syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.48

DEOGEN2

Uncertain

0.55

.;.;.;.;D;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

.;T;.;.;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.39

.;.;.;.;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.87

N;N;N;N;N;N

REVEL

Benign

0.27

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

0.96

T;T;T;T;T;.

Polyphen

0.0010

.;.;.;.;B;.

Vest4

0.016

MPC

0.035

ClinPred

0.0065

GERP RS

2.0

Varity_R

0.069

gMVP

0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over