rs386597997

Positions:

• chr11-17388025-T-G
• chr11-17388025-T-C
• chr11-17388025-T-A

Variant summary

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

The NM_000525.4(KCNJ11):​c.67A>C​(p.Lys23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 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. K23E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 67) in uniprot entity KCJ11_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000525.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07512206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.67A>C	p.Lys23Gln	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001377296.1	c.-24A>C		5_prime_UTR_variant	2/3		NP_001364225.1
KCNJ11	NM_001166290.2	c.-16-179A>C		intron_variant			NP_001159762.1
KCNJ11	NM_001377297.1	c.-16-179A>C		intron_variant			NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.67A>C	p.Lys23Gln	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.67
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.18
Sift	Benign	0.54	T
Sift4G	Benign	0.72	T
Vest4		0.035
MutPred		0.31		Loss of ubiquitination at K23 (P = 0.0412);
MVP		0.84
MPC		0.66
ClinPred		0.049	T
GERP RS		4.3
gMVP		0.45

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: rs5219; hg19: chr11-17409572;