11-2159886-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000207.3(INS):c.299G>A(p.Cys100Tyr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.12

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 Likely_pathogenic. Variant got 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 0 benign, 5 uncertain in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.299G>A	p.Cys100Tyr	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+899G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.299G>A	p.Cys100Tyr	missense_variant	3/3	1	NM_000207.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 23, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 2443150). This variant has not been reported in the literature in individuals affected with INS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 100 of the INS protein (p.Cys100Tyr). -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2022	DNA sequence analysis of the INS gene demonstrated a sequence change, c.299G>A, in exon 3 that results in an amino acid change, p.Cys100Tyr. This particular amino acid change does not appear to have been described in the literature in other individuals with INS-related disorders. This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Cys100Tyr amino acid change occurs in a region of the INS gene where other missense sequence changes have been described in individuals with INS-related disorders (PMIDs: 22957706, 2295770). A different missense change at the same amino acid residue (p. Cys100Gly) has been reported in a two-year-old individual with diabetes mellitus and was considered likely disease-causing by the authors (PMID: 31216263). Missense INS variants that cause a substitution or creation of a cysteine residue have been identified in multiple families with neonatal diabetes; these cysteine residue changes are predicted to lead to disruption of disulfide bridge formation critical for proinsulin folding (PMID: 18162506). The p.Cys100Tyr change affects a highly conserved amino acid residue located in a domain of the INS protein that is known to be functional. The p.Cys100Tyr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This collective evidence indicate that this sequence change is the likely pathogenic, however functional studies have not been performed to prove this conclusively -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-8.5	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.92		Gain of catalytic residue at C100 (P = 0.1173);Gain of catalytic residue at C100 (P = 0.1173);Gain of catalytic residue at C100 (P = 0.1173);.;
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2181116;