11-2160878-C-T

Position:

• chr11-2160878-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:3
• Conservation: PhyloP100: 5.58

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:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 id is 1338622.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21122.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=3, Pathogenic=4, Likely_pathogenic=1}. Variant chr11-2160878-C-T is described in Lovd as [Pathogenic]. Variant chr11-2160878-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.94G>A	p.Gly32Ser	missense_variant	2/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.153G>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.94G>A	p.Gly32Ser	missense_variant	2/3	1	NM_000207.3	P1

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

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Permanent neonatal diabetes mellitus Pathogenic:1 Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2021	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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2021	Published functional studies suggest a damaging effect on protein function (Park et al., 2010); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18840770, 17855560, 26530398, 31605659, 20034470, 31365591, 27634015, 19900242, 18162506, 32041611, 32792356, 31264968, 19952343) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	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. -

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

Uncertain significance, criteria provided, single submitter	research	Clinical 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 G32S/rs80356664 with Neonatal diabetes. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 18, 2007	- -

Neonatal diabetes mellitus Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Madras Diabetes Research Foundation	-	- -
not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2015	- -

Type 1 diabetes mellitus 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 04, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;.;.;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;.;D
Vest4		0.87
MVP		0.84
MPC		0.90
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.99

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

Other links and lift over

dbSNP: rs80356664; hg19: chr11-2182108;