rs59172778

chr11-128839231-A-Gchr11-128839231-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153766.3(KCNJ1):c.1013T>C(p.Met338Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0097 in 1,614,112 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (80 hom.)
• Consequence: KCNJ1 NM_153766.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 4.85

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 213) in uniprot entity KCNJ1_HUMAN there are 21 pathogenic changes around while only 4 benign (84%) in NM_153766.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.016446412).
• BP6: Variant 11-128839231-A-G is Benign according to our data. Variant chr11-128839231-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 9158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-128839231-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00766 (1167/152284) while in subpopulation NFE AF= 0.012 (817/68026). AF 95% confidence interval is 0.0113. There are 8 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ1	NM_153766.3	c.1013T>C	p.Met338Thr	missense_variant	3/3	ENST00000392666.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ1	ENST00000392666.6	c.1013T>C	p.Met338Thr	missense_variant	3/3	1	NM_153766.3	P1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152166 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00728 AC: 1830 AN: 251362 Hom.: 17 AF XY: 0.00738 AC XY: 1002 AN XY: 135854

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.00827

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00991 AC: 14492 AN: 1461828 Hom.: 80 Cov.: 33 AF XY: 0.00961 AC XY: 6988 AN XY: 727222

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.00844

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00778

GnomAD4 genome AF: 0.00766 AC: 1167 AN: 152284 Hom.: 8 Cov.: 32 AF XY: 0.00757 AC XY: 564 AN XY: 74468

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.00744

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00942 Hom.: 22

Bravo AF: 0.00672

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00943 AC: 81

ExAC AF: 0.00802 AC: 974

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00996

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 9580661, 20981092, 8841184, 27884173, 12589089, 28492530, 29191167) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 08, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

Bartter disease type 2 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1996	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 1.112% (rs59172778, 1491/129090 alleles, 14 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

KCNJ1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.86
Eigen	Benign	-0.0016
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	0.018	A;A;A;A;A
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.040	N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.39	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.0040	.;.;.;.;B
Vest4		0.56
MVP		0.82
MPC		0.039
ClinPred		0.026	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.43

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

Other links and lift over

dbSNP: rs59172778; hg19: chr11-128709126; COSMIC: COSV99047809; COSMIC: COSV99047809;