rs121908260

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

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

Scores

7
5
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 1.03
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a peptide Insulin B chain (size 29) in uniprot entity INS_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000207.3
PM2
Very rare variant in population databases, with high coverage;
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 id is 13391.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
INSNM_000207.3 linkuse as main transcriptc.137G>A p.Arg46Gln missense_variant 2/3 ENST00000381330.5 NP_000198.1 P01308-1I3WAC9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
INSENST00000381330.5 linkuse as main transcriptc.137G>A p.Arg46Gln missense_variant 2/31 NM_000207.3 ENSP00000370731.5 P01308-1
INS-IGF2ENST00000397270.1 linkuse as main transcriptc.137G>A p.Arg46Gln missense_variant 2/51 ENSP00000380440.1 F8WCM5-1

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
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
35

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 10 Pathogenic:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 2008- -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 28, 2023This 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 type (PMID: 18192540, 20226046, 28478482). 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
Uncertain significance, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-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;.;.;.;.;.
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
Polyphen
1.0
D;P;P;P;.;D
Vest4
0.74
MutPred
0.61
Loss of methylation at R46 (P = 0.0584);Loss of methylation at R46 (P = 0.0584);Loss of methylation at R46 (P = 0.0584);Loss of methylation at R46 (P = 0.0584);Loss of methylation at R46 (P = 0.0584);Loss of methylation at R46 (P = 0.0584);
MVP
0.82
MPC
0.81
ClinPred
0.99
D
GERP RS
1.9
Varity_R
0.87
gMVP
0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908260; hg19: chr11-2182065; COSMIC: COSV99171120; COSMIC: COSV99171120; API