11-128838528-G-A

Position:

• chr11-128838528-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_153766.3(KCNJ1):​c.*597C>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 0.0154 in 154,068 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., cov: 32)
  • Exomes 𝑓: 0.017 (0 hom.)
• Consequence: KCNJ1 NM_153766.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.46

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2338/152322) while in subpopulation NFE AF= 0.0227 (1543/68028). AF 95% confidence interval is 0.0217. There are 26 homozygotes in gnomad4. There are 1078 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ1	NM_153766.3	c.*597C>T		3_prime_UTR_variant	3/3	ENST00000392666.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ1	ENST00000392666.6	c.*597C>T		3_prime_UTR_variant	3/3	1	NM_153766.3	P1
KCNJ1	ENST00000324036.7	c.*597C>T		3_prime_UTR_variant	4/4	1		P1
KCNJ1	ENST00000392665.6	c.*597C>T		3_prime_UTR_variant	2/2	1		P1
KCNJ1	ENST00000440599.6	c.*597C>T		3_prime_UTR_variant	3/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2340 AN: 152204 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0224

GnomAD4 exome AF: 0.0172 AC: 30 AN: 1746 Hom.: 0 Cov.: 0 AF XY: 0.0170 AC XY: 17 AN XY: 1000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0153 AC: 2338 AN: 152322 Hom.: 26 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74480

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.0155

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Antenatal Bartter syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.32

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: rs117189807; hg19: chr11-128708423;