11-128839052-T-A

Variant names:

• chr11-128839052-T-A
• rs1231254
• NM_153766.3:c.*73A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153766.3(KCNJ1):​c.*73A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,397,342 control chromosomes in the GnomAD database, including 19,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2049 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17477 hom.)
• Consequence: KCNJ1 NM_153766.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0890
• Publications: 8 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-128839052-T-A is Benign according to our data. Variant chr11-128839052-T-A is described in ClinVar as [Benign]. Clinvar id is 303567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ1	NM_153766.3	c.*73A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000392666.6	NP_722450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ1	ENST00000392666.6	c.*73A>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_153766.3	ENSP00000376434.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24464 AN: 152062 Hom.: 2041 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.161 AC: 199941 AN: 1245162 Hom.: 17477 Cov.: 17 AF XY: 0.165 AC XY: 103901 AN XY: 628520

African (AFR) AF: 0.188 AC: 5513 AN: 29366

American (AMR) AF: 0.0875 AC: 3709 AN: 42402

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3576 AN: 24752

East Asian (EAS) AF: 0.0978 AC: 3769 AN: 38536

South Asian (SAS) AF: 0.299 AC: 23948 AN: 80152

European-Finnish (FIN) AF: 0.187 AC: 7667 AN: 41058

Middle Eastern (MID) AF: 0.143 AC: 760 AN: 5322

European-Non Finnish (NFE) AF: 0.153 AC: 142705 AN: 930164

Other (OTH) AF: 0.155 AC: 8294 AN: 53410

GnomAD4 genome AF: 0.161 AC: 24492 AN: 152180 Hom.: 2049 Cov.: 32 AF XY: 0.163 AC XY: 12161 AN XY: 74388

African (AFR) AF: 0.185 AC: 7683 AN: 41516

American (AMR) AF: 0.101 AC: 1547 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3472

East Asian (EAS) AF: 0.102 AC: 530 AN: 5188

South Asian (SAS) AF: 0.303 AC: 1459 AN: 4818

European-Finnish (FIN) AF: 0.198 AC: 2091 AN: 10570

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10257 AN: 68002

Other (OTH) AF: 0.149 AC: 314 AN: 2114

Alfa AF: 0.153 Hom.: 201

Bravo AF: 0.153

Asia WGS AF: 0.188 AC: 653 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Antenatal Bartter syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.68
DANN	Benign	0.50
PhyloP100		-0.089
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1231254; hg19: chr11-128708947;