rs567313382

Variant names:

• chr11-17372437-ACCT-A
• rs567313382
• NM_001202439.3:c.1296_1298delTCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001202439.3(NCR3LG1):​c.1296_1298delTCC​(p.Pro433del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 703,126 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: NCR3LG1 NM_001202439.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.206
• Publications: 1 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 -6 ACMG points.

• BP6: Variant 11-17372437-ACCT-A is Benign according to our data. Variant chr11-17372437-ACCT-A is described in ClinVar as [Likely_benign]. Clinvar id is 3388185.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3LG1	NM_001202439.3	c.1296_1298delTCC	p.Pro433del	disruptive_inframe_deletion	Exon 5 of 5	ENST00000338965.9	NP_001189368.1
NCR3LG1	XM_047426906.1	c.1296_1298delTCC	p.Pro433del	disruptive_inframe_deletion	Exon 5 of 6		XP_047282862.1
NCR3LG1	XM_011520074.4	c.1209_1211delTCC	p.Pro404del	disruptive_inframe_deletion	Exon 5 of 5		XP_011518376.1
NCR3LG1	XM_011520075.4	c.1209_1211delTCC	p.Pro404del	disruptive_inframe_deletion	Exon 5 of 5		XP_011518377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3LG1	ENST00000338965.9	c.1296_1298delTCC	p.Pro433del	disruptive_inframe_deletion	Exon 5 of 5	1	NM_001202439.3	ENSP00000341637.4
NCR3LG1	ENST00000530403.1	n.1296_1298delTCC		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000434394.1
KCNJ11	ENST00000682764.1	c.*51-6138_*51-6136delAGG		intron_variant	Intron 2 of 2			ENSP00000506780.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00482

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00232 AC: 321 AN: 138140 AF XY: 0.00245

Gnomad AFR exome AF: 0.000595

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00279 AC: 1540 AN: 550988 Hom.: 5 AF XY: 0.00267 AC XY: 795 AN XY: 298254

African (AFR) AF: 0.00108 AC: 17 AN: 15806

American (AMR) AF: 0.000806 AC: 28 AN: 34718

Ashkenazi Jewish (ASJ) AF: 0.0000999 AC: 2 AN: 20020

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.00183 AC: 115 AN: 62774

European-Finnish (FIN) AF: 0.000919 AC: 31 AN: 33736

Middle Eastern (MID) AF: 0.000490 AC: 2 AN: 4078

European-Non Finnish (NFE) AF: 0.00398 AC: 1263 AN: 317034

Other (OTH) AF: 0.00267 AC: 82 AN: 30718

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152138 Hom.: 1 Cov.: 32 AF XY: 0.00237 AC XY: 176 AN XY: 74368

African (AFR) AF: 0.00108 AC: 45 AN: 41518

American (AMR) AF: 0.000589 AC: 9 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4810

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00482 AC: 328 AN: 67980

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00254

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NCR3LG1: PM4:Supporting, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=88/12	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: rs567313382; hg19: chr11-17393984;