11-17367161-G-A

Variant names:

• chr11-17367161-G-A
• rs1389365668
• NM_001202439.3:c.574G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001202439.3(NCR3LG1):​c.574G>A​(p.Glu192Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,384,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: NCR3LG1 NM_001202439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.580
• Publications: 0 publications found

Genes affected

NCR3LG1 (HGNC:42400): (natural killer cell cytotoxicity receptor 3 ligand 1) B7H6 belongs to the B7 family (see MIM 605402) and is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3; MIM 611550) results in natural killer (NK) cell activation and cytotoxicity (Brandt et al., 2009 [PubMed 19528259]).[supplied by OMIM, Jan 2011]

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]

KCNJ11 Gene-Disease associations (from GenCC):

• diabetes mellitus, transient neonatal, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hyperinsulinemic hypoglycemia, familial, 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• diabetes mellitus, permanent neonatal 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 13

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1272138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3	c.574G>A	p.Glu192Lys	missense_variant	Exon 3 of 5	ENST00000338965.9	NP_001189368.1
NCR3LG1	XM_047426906.1	c.574G>A	p.Glu192Lys	missense_variant	Exon 3 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4	c.487G>A	p.Glu163Lys	missense_variant	Exon 3 of 5		XP_011518376.1
NCR3LG1	XM_011520075.4	c.487G>A	p.Glu163Lys	missense_variant	Exon 3 of 5		XP_011518377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3LG1	ENST00000338965.9	c.574G>A	p.Glu192Lys	missense_variant	Exon 3 of 5	1	NM_001202439.3	ENSP00000341637.4
NCR3LG1	ENST00000530403.1	n.574G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000434394.1
KCNJ11	ENST00000682764.1	c.*51-859C>T		intron_variant	Intron 2 of 2			ENSP00000506780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000708 AC: 1 AN: 141302 AF XY: 0.0000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000491 AC: 68 AN: 1384310 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 37 AN XY: 683064

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34086

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.0000612 AC: 66 AN: 1079004

Other (OTH) AF: 0.0000172 AC: 1 AN: 58064

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574G>A (p.E192K) alteration is located in exon 3 (coding exon 3) of the NCR3LG1 gene. This alteration results from a G to A substitution at nucleotide position 574, causing the glutamic acid (E) at amino acid position 192 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.58
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.072
Sift	Benign	0.37	T
Sift4G	Benign	0.15	T
Polyphen		0.17	B
Vest4		0.047
MutPred		0.57		Gain of ubiquitination at E192 (P = 0.0104);
MVP		0.040
ClinPred		0.058	T
GERP RS		0.35
Varity_R		0.24
gMVP		0.47
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: rs1389365668; hg19: chr11-17388708;