rs770408379

chr11-17387075-C-Achr11-17387075-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000525.4(KCNJ11):c.1017G>T(p.Val339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,086 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). Synonymous variant affecting the same amino acid position (i.e. V339V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: KCNJ11 NM_000525.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.614

Genes affected

KCNJ11 (HGNC:6257): (potassium inwardly rectifying channel subfamily J member 11) 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. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-17387075-C-A is Benign according to our data. Variant chr11-17387075-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211219.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.614 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000274 (40/1461880) while in subpopulation AFR AF= 0.000866 (29/33480). AF 95% confidence interval is 0.000619. There are 0 homozygotes in gnomad4_exome. There are 21 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.1017G>T	p.Val339=	synonymous_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.756G>T	p.Val252=	synonymous_variant	2/2
KCNJ11	NM_001377296.1	c.756G>T	p.Val252=	synonymous_variant	3/3
KCNJ11	NM_001377297.1	c.756G>T	p.Val252=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1017G>T	p.Val339=	synonymous_variant	1/1		NM_000525.4	P1
KCNJ11	ENST00000528731.1	c.756G>T	p.Val252=	synonymous_variant	2/2	1
KCNJ11	ENST00000682350.1	c.756G>T	p.Val252=	synonymous_variant	2/2
KCNJ11	ENST00000682764.1	c.756G>T	p.Val252=	synonymous_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251476 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727240

Gnomad4 AFR exome AF: 0.000866

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: 0.00000270

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152206 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74364

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	7.5
Dann	Benign	0.89

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: rs770408379; hg19: chr11-17408622;