rs80356666

Variant names:

• chr11-2160845-A-C
• rs80356666
• NM_000207.3:c.127T>G

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.127T>G​(p.Cys43Gly) variant causes a missense change. 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 risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C43W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:3 O:3
• Conservation: PhyloP100: 4.29
• Publications: 15 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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chr11-2160843-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3773933.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, 0.983
• PP5: Variant 11-2160845-A-C is Pathogenic according to our data. Variant chr11-2160845-A-C is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 21114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.127T>G	p.Cys43Gly	missense_variant	Exon 2 of 3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.127T>G	p.Cys43Gly	missense_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.127T>G	p.Cys43Gly	missense_variant	Exon 2 of 5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 89

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:3 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Permanent neonatal diabetes mellitus Other:2

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Type 2 diabetes mellitus Pathogenic:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely risk allele

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in theINS 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 C43G/ rs80356666 with Diabetes mellitus.

Diabetes mellitus, permanent neonatal 4 Pathogenic:1

Sep 18, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Sep 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36830626, 17047922, 18171712, 18162506, 20724178, 37048081, 24843647, 30177968, 20938745, 19952343, 17855560, 20034470, 36028536)

Neonatal diabetes mellitus Other:1

Oct 02, 2015

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

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;D;D;D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;.;.;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.
PhyloP100		4.3
PROVEAN	Pathogenic	-11	D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D
Vest4		0.95
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		0.016	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs80356666; hg19: chr11-2182075;