rs121908260

Variant names:

• chr11-2160835-C-T
• rs121908260
• NM_000207.3:c.137G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000207.3(INS):​c.137G>A​(p.Arg46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,352 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 1.03
• Publications: 26 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 9 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
• 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, 0.905
• PP5: Variant 11-2160835-C-T is Pathogenic according to our data. Variant chr11-2160835-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13391.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.137G>A	p.Arg46Gln	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.137G>A	p.Arg46Gln	missense_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.137G>A	p.Arg46Gln	missense_variant	Exon 2 of 5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460352 Hom.: 0 Cov.: 88 AF XY: 0.00000275 AC XY: 2 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 10 Pathogenic:1 Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apr 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the INS protein (p.Arg46Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 18192540, 20226046, 28478482, 34789499). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13391). 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: 20948967, 25423173). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Diabetes mellitus, permanent neonatal 4 Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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 R46Q/ rs121908260 with permanent neonatal diabetes mellitus.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;D;D;D;.;.
Eigen	Benign	0.091
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.95	D;.;.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.
PhyloP100		1.0
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;.;D
Vest4		0.74
ClinPred		0.99	D
GERP RS		1.9
PromoterAI		-0.0033	Neutral
Varity_R		0.58
gMVP		0.94
Mutation Taster		=6/94	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: rs121908260; hg19: chr11-2182065; COSMIC: COSV99171120; COSMIC: COSV99171120;