11-17368871-T-C

Variant names:

• chr11-17368871-T-C
• NM_001202439.3:c.765T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001202439.3(NCR3LG1):​c.765T>C​(p.Thr255Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,377,140 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NCR3LG1 NM_001202439.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.223
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17368871-T-C is Benign according to our data. Variant chr11-17368871-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3771785.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3	c.765T>C	p.Thr255Thr	synonymous_variant	Exon 4 of 5	ENST00000338965.9	NP_001189368.1
NCR3LG1	XM_047426906.1	c.765T>C	p.Thr255Thr	synonymous_variant	Exon 4 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4	c.678T>C	p.Thr226Thr	synonymous_variant	Exon 4 of 5		XP_011518376.1
NCR3LG1	XM_011520075.4	c.678T>C	p.Thr226Thr	synonymous_variant	Exon 4 of 5		XP_011518377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3LG1	ENST00000338965.9	c.765T>C	p.Thr255Thr	synonymous_variant	Exon 4 of 5	1	NM_001202439.3	ENSP00000341637.4
NCR3LG1	ENST00000530403.1	n.765T>C		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000434394.1
KCNJ11	ENST00000682764.1	c.*51-2569A>G		intron_variant	Intron 2 of 2			ENSP00000506780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1377140 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 680072

African (AFR) AF: 0.00 AC: 0 AN: 31374

American (AMR) AF: 0.00 AC: 0 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 35708

South Asian (SAS) AF: 0.00 AC: 0 AN: 78978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072860

Other (OTH) AF: 0.00 AC: 0 AN: 57858

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NCR3LG1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.37
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: chr11-17390418;