11-2160878-C-T

Variant names:

• chr11-2160878-C-T
• rs80356664
• NM_000207.3:c.94G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000207.3(INS):​c.94G>A​(p.Gly32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G32R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:3
• Conservation: PhyloP100: 5.58
• Publications: 49 publications found

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2160877-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1338622.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.9004 (below the threshold of 3.09). Trascript score misZ: 0.85584 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperproinsulinemia, diabetes mellitus, permanent neonatal 4, type 1 diabetes mellitus 2, maturity-onset diabetes of the young type 10, monogenic diabetes, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 11-2160878-C-T is Pathogenic according to our data. Variant chr11-2160878-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.94G>A	p.Gly32Ser	missense	Exon 2 of 3	NP_000198.1
	INS-IGF2	NM_001042376.3		c.94G>A	p.Gly32Ser	missense	Exon 2 of 5	NP_001035835.1
	INS	NM_001185097.2		c.94G>A	p.Gly32Ser	missense	Exon 2 of 3	NP_001172026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.94G>A	p.Gly32Ser	missense	Exon 2 of 3	ENSP00000370731.5
	INS-IGF2	ENST00000397270.1	TSL:1	c.94G>A	p.Gly32Ser	missense	Exon 2 of 5	ENSP00000380440.1
	INS	ENST00000250971.7	TSL:1	c.94G>A	p.Gly32Ser	missense	Exon 2 of 3	ENSP00000250971.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460384 Hom.: 0 Cov.: 88 AF XY: 0.00000138 AC XY: 1 AN XY: 726528

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 35

Alfa AF: 0.00000503 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes mellitus, permanent neonatal 4 Pathogenic:2 Uncertain:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

Sep 18, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.Sufficient evidence is found to confer the association of this particular variant G32S/rs80356664 with Neonatal diabetes.

Permanent neonatal diabetes mellitus Pathogenic:1 Other:2

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jul 21, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly32Ser variant in INS has been reported in at least 15 individuals with early-onset or infantile diabetes, including 8 de novo occurrences, and segregated with disease in 4 affected individuals from 1 family (Stoy 2007 PMID:17855560, Edghill 2008 PMID: 18162506, Bonfanti 2009 PMID: 18840770, Rubio-Cabezas 2009 PMID: 19900242, Jahnavi 2013 PMID: 22831748, Globa 2015 PMID: 26208381, Ortolani 2015 PMID: 26239141, Brahm 2016 PMID: 27634015, Wasserman 2016 PMID: 26530398, Urrutia 2019 PMID: 31365591, Fu 2020 PMID: 31605659, Lin 2020 PMID: 32792356). It was absent from large population studies but has been reported in ClinVar (Variation ID 21122). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Park 2010 PMID: 20034470, Rajan 2010 PMID: 19952343). Animal models in mice support that this variant causes diabetes (Austin 2020 PMID: 32994272). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant monogenic diabetes. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2_Supporting, PS3_Moderate, PP1, PP3.

not provided Pathogenic:2

Jun 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect on protein function (PMID: 20034470); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17855560, 18162506, 19900242, 27634015, 31365591, 31605659, 18840770, 19952343, 26530398, 31264968, 32792356, 32041611, 37897565, 37048081, 36398453, 36151994, 36504295, 36724370, 36418577, 34387403, 38793013, 36655002, 35518939, 20034470)

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 32 of the INS protein (p.Gly32Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant permanent neonatal diabetes mellitus (PMID: 17855560). 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. ClinVar contains an entry for this variant (Variation ID: 21122). 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. Experimental studies have shown that this missense change affects INS function (PMID: 19952343). For these reasons, this variant has been classified as Pathogenic.

Neonatal diabetes mellitus Pathogenic:1 Other:1

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 03, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Type 1 diabetes mellitus 2 Pathogenic:1

Nov 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N
PhyloP100		5.6
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.84
MPC		0.90
ClinPred		1.0	D
GERP RS		3.9
PromoterAI		-0.0016	Neutral
Varity_R		0.87
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80356664; hg19: chr11-2182108;