11-128839109-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28

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 -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. Variant chr11-128839109-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ1	NM_153766.3	c.*16G>A		3_prime_UTR_variant	3/3	ENST00000392666.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ1	ENST00000392666.6	c.*16G>A		3_prime_UTR_variant	3/3	1	NM_153766.3	P1

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152136 Hom.: 6 Cov.: 32

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

GnomAD3 exomes AF: 0.00545 AC: 1360 AN: 249756 Hom.: 6 AF XY: 0.00543 AC XY: 734 AN XY: 135154

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 SAS exome AF: 0.000458

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.: 61 Cov.: 31 AF XY: 0.00712 AC XY: 5166 AN XY: 725610

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.00837

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152254 Hom.: 6 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74446

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.00838

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00512 Hom.: 0

Bravo AF: 0.00417

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartter disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.21
Dann	Benign	0.75

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: rs3181542; hg19: chr11-128709004;