11-128839709-C-T

Position:

• chr11-128839709-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_153766.3(KCNJ1):​c.535G>A​(p.Ala179Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: KCNJ1 NM_153766.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.89

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-128839709-C-T is Pathogenic according to our data. Variant chr11-128839709-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ1	NM_153766.3	c.535G>A	p.Ala179Thr	missense_variant	3/3	ENST00000392666.6	NP_722450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ1	ENST00000392666.6	c.535G>A	p.Ala179Thr	missense_variant	3/3	1	NM_153766.3	ENSP00000376434	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461060 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartter disease type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the KCNJ1 protein (p.Ala198Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Bartter syndrome (PMID: 9002665). It has also been observed to segregate with disease in related individuals. This variant is also known as G‚ÜíA at 1153. ClinVar contains an entry for this variant (Variation ID: 9159). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNJ1 function (PMID: 9015377, 12911542, 19221509, 28630040). This variant disrupts the p.Ala198 amino acid residue in KCNJ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ1-related conditions (PMID: 20219833), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Bartter syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2024

Variant summary: KCNJ1 c.592G>A (p.Ala198Thr) results in a non-conservative amino acid change located in the Potassium channel, inwardly rectifying, transmembrane domain (IPR040445) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.592G>A has been reported in the literature in at-least two individuals affected with Bartter Syndrome (example, Karolyi_1997). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal KCNJ1 levels in yeast (ODonnell_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28630040, 9002665). ClinVar contains an entry for this variant (Variation ID: 9159). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;.;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.94
MutPred		0.95		.;.;.;.;Loss of catalytic residue at A198 (P = 0.004);
MVP		0.93
MPC		0.26
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.95

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: rs104894253; hg19: chr11-128709604; COSMIC: COSV60662134; COSMIC: COSV60662134;