11-17367299-C-G

Variant names:

• chr11-17367299-C-G
• NM_001202439.3:c.712C>G

Variant summary

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

The NM_001202439.3(NCR3LG1):​c.712C>G​(p.Pro238Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 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)
• Consequence: NCR3LG1 NM_001202439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.63
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3	c.712C>G	p.Pro238Ala	missense_variant	Exon 3 of 5	ENST00000338965.9	NP_001189368.1
NCR3LG1	XM_047426906.1	c.712C>G	p.Pro238Ala	missense_variant	Exon 3 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4	c.625C>G	p.Pro209Ala	missense_variant	Exon 3 of 5		XP_011518376.1
NCR3LG1	XM_011520075.4	c.625C>G	p.Pro209Ala	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.712C>G	p.Pro238Ala	missense_variant	Exon 3 of 5	1	NM_001202439.3	ENSP00000341637.4
NCR3LG1	ENST00000530403.1	n.712C>G		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000434394.1
KCNJ11	ENST00000682764.1	c.*51-997G>C		intron_variant	Intron 2 of 2			ENSP00000506780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712C>G (p.P238A) alteration is located in exon 3 (coding exon 3) of the NCR3LG1 gene. This alteration results from a C to G substitution at nucleotide position 712, causing the proline (P) at amino acid position 238 to be replaced by an alanine (A). 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	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.011
DANN	Benign	0.49
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.0043	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-3.6
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.084
Sift	Benign	0.049	D
Sift4G	Benign	0.39	T
Polyphen		0.12	B
Vest4		0.14
MutPred		0.84		Gain of methylation at R240 (P = 0.0803);
MVP		0.040
ClinPred		0.12	T
GERP RS		-8.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.22
Mutation Taster		=100/0	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

hg19: chr11-17388846;