11-128838456-T-C

Variant names:

• chr11-128838456-T-C
• rs113342294
• NM_153766.3:c.*669A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153766.3(KCNJ1):​c.*669A>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 0.0363 in 152,316 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (319 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNJ1 NM_153766.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ1	NM_153766.3	c.*669A>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.*669A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_153766.3	ENSP00000376434.1
KCNJ1	ENST00000324036.7	c.*669A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000316233.3
KCNJ1	ENST00000392665.6	c.*669A>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000376433.2
KCNJ1	ENST00000440599.6	c.*669A>G		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000406320.2

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5520 AN: 152198 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0292

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 298 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 168

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 20

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 262

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0363 AC: 5522 AN: 152316 Hom.: 319 Cov.: 32 AF XY: 0.0350 AC XY: 2608 AN XY: 74486

African (AFR) AF: 0.123 AC: 5123 AN: 41550

American (AMR) AF: 0.0162 AC: 248 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68028

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0304 Hom.: 61

Bravo AF: 0.0422

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Antenatal Bartter syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.85
CADD	Benign	4.0
DANN	Benign	0.60
PhyloP100		1.4
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: rs113342294; hg19: chr11-128708351;