rs59172778

Variant names:

• chr11-128839231-A-G
• rs59172778
• NM_153766.3:c.1013T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-128839231-A-G
• chr11-128839231-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153766.3(KCNJ1):​c.1013T>C​(p.Met338Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0097 in 1,614,112 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (80 hom.)
• Consequence: KCNJ1 NM_153766.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 4.85
• Publications: 25 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• antenatal Bartter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -0.27693 (below the threshold of 3.09). Trascript score misZ: 0.38698 (below the threshold of 3.09). GenCC associations: The gene is linked to antenatal Bartter syndrome, Bartter disease type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016446412).
• BP6: Variant 11-128839231-A-G is Benign according to our data. Variant chr11-128839231-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 9158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00766 (1167/152284) while in subpopulation NFE AF = 0.012 (817/68026). AF 95% confidence interval is 0.0113. There are 8 homozygotes in GnomAd4. There are 564 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153766.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ1	NM_153766.3	MANE Select	c.1013T>C	p.Met338Thr	missense	Exon 3 of 3	NP_722450.1	P48048-2
	KCNJ1	NM_000220.6		c.1070T>C	p.Met357Thr	missense	Exon 2 of 2	NP_000211.1	P48048-1
	KCNJ1	NM_153765.3		c.1064T>C	p.Met355Thr	missense	Exon 3 of 3	NP_722449.3	P48048-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ1	ENST00000392666.6	TSL:1 MANE Select	c.1013T>C	p.Met338Thr	missense	Exon 3 of 3	ENSP00000376434.1	P48048-2
	KCNJ1	ENST00000392664.2	TSL:1	c.1070T>C	p.Met357Thr	missense	Exon 2 of 2	ENSP00000376432.2	P48048-1
	KCNJ1	ENST00000324036.7	TSL:1	c.1013T>C	p.Met338Thr	missense	Exon 4 of 4	ENSP00000316233.3	P48048-2

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152166 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00728 AC: 1830 AN: 251362 AF XY: 0.00738

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00827

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00991 AC: 14492 AN: 1461828 Hom.: 80 Cov.: 33 AF XY: 0.00961 AC XY: 6988 AN XY: 727222

African (AFR) AF: 0.00215 AC: 72 AN: 33478

American (AMR) AF: 0.00376 AC: 168 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00319 AC: 275 AN: 86256

European-Finnish (FIN) AF: 0.00844 AC: 451 AN: 53418

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 12959 AN: 1111956

Other (OTH) AF: 0.00778 AC: 470 AN: 60394

GnomAD4 genome AF: 0.00766 AC: 1167 AN: 152284 Hom.: 8 Cov.: 32 AF XY: 0.00757 AC XY: 564 AN XY: 74468

African (AFR) AF: 0.00257 AC: 107 AN: 41556

American (AMR) AF: 0.00726 AC: 111 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4814

European-Finnish (FIN) AF: 0.00744 AC: 79 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 817 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00926 Hom.: 33

Bravo AF: 0.00672

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00943 AC: 81

ExAC AF: 0.00802 AC: 974

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
1	-	1	Bartter disease type 2 (2)
-	-	1	KCNJ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.0016
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.39
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.0040	B
Vest4		0.56
MVP		0.82
MPC		0.039
ClinPred		0.026	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.43
Mutation Taster		=99/1	polymorphism

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: rs59172778; hg19: chr11-128709126; COSMIC: COSV99047809; COSMIC: COSV99047809;