chr11-17387284-G-T

Variant names:

• chr11-17387284-G-T
• rs1800467
• NM_000525.4:c.808C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000525.4(KCNJ11):​c.808C>A​(p.Leu270Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L270V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19730473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.808C>A	p.Leu270Met	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.547C>A	p.Leu183Met	missense_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.547C>A	p.Leu183Met	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.547C>A	p.Leu183Met	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.808C>A	p.Leu270Met	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251334 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461886 Hom.: 0 Cov.: 69 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000660 Hom.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	0.088
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T;.
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.20	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.35	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.87	T;T
Sift4G	Benign	0.75	T;T
Vest4		0.14
MVP		0.97
MPC		0.62
ClinPred		0.37	T
GERP RS		5.4
gMVP		0.46

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: rs1800467; hg19: chr11-17408831;