11-2159920-G-A

Position:

• chr11-2159920-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000207.3(INS):​c.265C>T​(p.Arg89Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:2
• Conservation: PhyloP100: 0.612

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

INS-IGF2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a disulfide_bond Interchain (between B and A chains) (size 65) in uniprot entity INS_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 11-2159920-G-A is Pathogenic according to our data. Variant chr11-2159920-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2159920-G-A is described in Lovd as [Pathogenic]. Variant chr11-2159920-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.265C>T	p.Arg89Cys	missense_variant	3/3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.265C>T	p.Arg89Cys	missense_variant	3/3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.187+865C>T		intron_variant		1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450698 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Permanent neonatal diabetes mellitus Pathogenic:1 Other:2

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Published in vitro functional studies suggest a negative effect on subcellular insulin localization and incomplete processing of proinsulin to insulin, but no inhibition of wildtype insulin secretion (Rajan et al., 2010); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28597946, 23074673, 23771172, 18162506, 20034470, 22957706, 17855560, 19900242, 28667717, 23050777, 25555642, 18171712, 28323911, 31605659, 35518939, 34593315, 32792356, 19952343) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560, 22957706). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the INS protein (p.Arg89Cys). ClinVar contains an entry for this variant (Variation ID: 21117). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Diabetes mellitus, permanent neonatal 4 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as potent mutations in this gene can cause beta cell destruction.However, more evidence is required to confer the association of this particular variant R89C/ rs80356669 with Permanent neonatal diabetes mellitus(PNDM) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -

Neonatal diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

-

- -

INS-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The INS c.265C>T variant is predicted to result in the amino acid substitution p.Arg89Cys. This variant, also known as p.Arg65Cys using legacy nomenclature, has been reported in several individuals, often occurring de novo, with permanent neonatal diabetes (Støy et al. 2007. PubMed ID: 17855560; Moritani et al. 2012. PubMed ID: 22957706; Fu et al. 2019. PubMed ID: 31605659; Lin Y et al 2020. PubMed ID: 32792356; Globa et al. 2022. PubMed ID: 36398453). In vitro studies demonstrate that expression of this variant results in aberrant processing of proinsulin to insulin and retainment in the endoplasmic reticulum (Rajan et al. 2009. PubMed ID: 19952343; Park et al. 2009. PubMed ID: 20034470). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, different missense changes impacting the same amino acid (p.Arg89Pro, p.Arg89His, and p.Arg89Leu) have also been reported in association with hyperproinsulinemia and diabetes (Robbins et al. 1984. PubMed ID: 6368587; Billings et al. 2022. PubMed ID: 36208030). Taken together, the c.265C>T (p.Arg89Cys) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.8	H;H;H;.
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.85
MutPred		0.81		Gain of methylation at K88 (P = 0.0249);Gain of methylation at K88 (P = 0.0249);Gain of methylation at K88 (P = 0.0249);.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.89
gMVP		0.97

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: rs80356669; hg19: chr11-2181150;