Genetic Variant NM_153766.3:c.199A>G (chr11-128840045-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 16/21 in silico tools predict 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. T67T) has been classified 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

Publications

10 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -0.27693 (below the threshold of 3.09). Trascript score misZ: 0.38698 (below the threshold of 3.09). GenCC associations: The gene is linked to antenatal Bartter syndrome, Bartter disease type 2.

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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153766.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNJ1	NM_153766.3	MANE Select	c.199A>G	p.Thr67Ala	missense	Exon 3 of 3	NP_722450.1	P48048-2
KCNJ1	NM_000220.6		c.256A>G	p.Thr86Ala	missense	Exon 2 of 2	NP_000211.1	P48048-1
KCNJ1	NM_153765.3		c.250A>G	p.Thr84Ala	missense	Exon 3 of 3	NP_722449.3	P48048-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNJ1	ENST00000392666.6	TSL:1 MANE Select	c.199A>G	p.Thr67Ala	missense	Exon 3 of 3	ENSP00000376434.1	P48048-2
KCNJ1	ENST00000392664.2	TSL:1	c.256A>G	p.Thr86Ala	missense	Exon 2 of 2	ENSP00000376432.2	P48048-1
KCNJ1	ENST00000324036.7	TSL:1	c.199A>G	p.Thr67Ala	missense	Exon 4 of 4	ENSP00000316233.3	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

GnomAD2 exomes

AF:

0.0221

AC:

5549

AN:

251256

AF XY:

0.0165

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 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

African (AFR)

AF:

0.00105

AC:

AN:

33476

American (AMR)

AF:

0.135

AC:

6053

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000880

AC:

AN:

26132

East Asian (EAS)

AF:

0.0159

AC:

631

AN:

39700

South Asian (SAS)

AF:

0.00146

AC:

126

AN:

86256

European-Finnish (FIN)

AF:

0.00367

AC:

196

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000231

AC:

257

AN:

1111994

Other (OTH)

AF:

0.00444

AC:

268

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

450

901

1351

1802

2252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00910

AC:

1386

AN:

152298

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

806

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41564

American (AMR)

AF:

0.0742

AC:

1136

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0114

AC:

AN:

5190

South Asian (SAS)

AF:

0.00290

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00547

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68018

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00299

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Antenatal Bartter syndrome (1)

KCNJ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.48

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.39

PhyloP100

1.4

PrimateAI

Benign

0.42

PROVEAN

Benign

0.87

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

0.96

Polyphen

0.0010

Vest4

0.016

MPC

0.035

ClinPred

0.0065

GERP RS

2.0

Varity_R

0.069

gMVP

0.61

Mutation Taster

=98/2

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