11-128838080-G-C

Variant names:

• chr11-128838080-G-C
• rs675759
• NM_153766.3:c.*1045C>G

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.*1045C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,592 control chromosomes in the GnomAD database, including 2,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2009 hom., cov: 32)
  • Exomes 𝑓: 0.20 (10 hom.)
• Consequence: KCNJ1 NM_153766.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.700
• Publications: 9 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=-0.84).
• BP6: Variant 11-128838080-G-C is Benign according to our data. Variant chr11-128838080-G-C is described in ClinVar as [Benign]. Clinvar id is 303553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ1	NM_153766.3	c.*1045C>G		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.*1045C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_153766.3	ENSP00000376434.1
KCNJ1	ENST00000392665.6	c.*1045C>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000376433.2
KCNJ1	ENST00000440599.6	c.*1045C>G		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000406320.2
KCNJ1	ENST00000324036.7	c.*1045C>G		downstream_gene_variant		1		ENSP00000316233.3

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24282 AN: 152090 Hom.: 2004 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.202 AC: 78 AN: 386 Hom.: 10 Cov.: 0 AF XY: 0.196 AC XY: 44 AN XY: 224

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.203 AC: 77 AN: 380

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.160 AC: 24308 AN: 152206 Hom.: 2009 Cov.: 32 AF XY: 0.162 AC XY: 12073 AN XY: 74426

African (AFR) AF: 0.181 AC: 7533 AN: 41524

American (AMR) AF: 0.101 AC: 1542 AN: 15298

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

East Asian (EAS) AF: 0.102 AC: 530 AN: 5186

South Asian (SAS) AF: 0.296 AC: 1428 AN: 4824

European-Finnish (FIN) AF: 0.198 AC: 2102 AN: 10598

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.151 AC: 10249 AN: 67988

Other (OTH) AF: 0.148 AC: 313 AN: 2112

Alfa AF: 0.154 Hom.: 229

Bravo AF: 0.152

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Antenatal Bartter syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.54
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs675759; hg19: chr11-128707975;