11-2159877-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000207.3(INS):c.308A>G(p.Tyr103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 1.84

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 7 ACMG points.

• PM1: In a hotspot region, there are 7 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 11-2159877-T-C is Pathogenic according to our data. Variant chr11-2159877-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68732.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_risk_allele=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.308A>G	p.Tyr103Cys	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+908A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.308A>G	p.Tyr103Cys	missense_variant	3/3	1	NM_000207.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Permanent neonatal diabetes mellitus Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 28, 2017	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Diabetes mellitus, permanent neonatal 4 Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. It may have poor response to sulfonylureas, as mutations in this gene can cause beta cell destruction. Sufficient evidence is found to confer the association of this particular variant rs121908277 with permanent neonatal diabetes mellitus. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2021

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 103 of the INS protein (p.Tyr103Cys). 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 and/or INS-related conditions (PMID: 18162506, 30191644). ClinVar contains an entry for this variant (Variation ID: 68732). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.4	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.60
MutPred		0.51		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.94
MPC		1.3
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.97
gMVP		0.88

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: rs121908277; hg19: chr11-2181107;