rs372447456

chr11-128911406-G-Achr11-128911406-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000890.5(KCNJ5):c.133G>A(p.Glu45Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E45Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 8.15

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18963996).
• BP6: Variant 11-128911406-G-A is Benign according to our data. Variant chr11-128911406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190825.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr11-128911406-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ5	NM_000890.5	c.133G>A	p.Glu45Lys	missense_variant	2/3	ENST00000529694.6
KCNJ5	NM_001354169.2	c.133G>A	p.Glu45Lys	missense_variant	3/4
KCNJ5	XM_011542810.4	c.133G>A	p.Glu45Lys	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ5	ENST00000529694.6	c.133G>A	p.Glu45Lys	missense_variant	2/3	1	NM_000890.5	P1
KCNJ5	ENST00000338350.4	c.133G>A	p.Glu45Lys	missense_variant	3/4	1		P1
KCNJ5	ENST00000533599.1	c.133G>A	p.Glu45Lys	missense_variant	1/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251444 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135906

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74506

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000121

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	This variant is associated with the following publications: (PMID: 28767663) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2020	- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Benign	0.85	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.45	B;B;B
Vest4		0.28
MVP		0.88
MPC		0.48
ClinPred		0.079	T
GERP RS		5.5
Varity_R		0.19
gMVP		0.63

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: rs372447456; hg19: chr11-128781301; COSMIC: COSV57965477;