rs748305494

chr11-128839210-T-Cchr11-128839210-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_153766.3(KCNJ1):c.1034A>G(p.Asp345Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,614,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: KCNJ1 NM_153766.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 213) in uniprot entity KCNJ1_HUMAN there are 21 pathogenic changes around while only 4 benign (84%) in NM_153766.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08330938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ1	NM_153766.3	c.1034A>G	p.Asp345Gly	missense_variant	3/3	ENST00000392666.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ1	ENST00000392666.6	c.1034A>G	p.Asp345Gly	missense_variant	3/3	1	NM_153766.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251366 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461868 Hom.: 1 Cov.: 33 AF XY: 0.0000921 AC XY: 67 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2020

The c.1091A>G (p.D364G) alteration is located in exon 2 (coding exon 2) of the KCNJ1 gene. This alteration results from a A to G substitution at nucleotide position 1091, causing the aspartic acid (D) at amino acid position 364 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD) database, the KCNJ1 c.1091A>G alteration was observed in 0.01% (26/282760) of total alleles studied. This amino acid position is not well conserved in available vertebrate species. The p.D364G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bartter disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	18
Dann	Benign	0.55
Eigen	Benign	-0.097
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.64	T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T
Polyphen		0.0010	.;.;.;.;B
Vest4		0.086
MutPred		0.45		.;.;.;.;Gain of helix (P = 0.0225);
MVP		0.82
MPC		0.19
ClinPred		0.045	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.69

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: rs748305494; hg19: chr11-128709105;