rs1057524907

chr11-2159907-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000207.3(INS):c.278A>G(p.Glu93Gly) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E93K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 O:1
• Conservation: PhyloP100: 2.73

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 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 11-2159907-T-C is Pathogenic according to our data. Variant chr11-2159907-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393455.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_risk_allele=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.278A>G	p.Glu93Gly	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+878A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.278A>G	p.Glu93Gly	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:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Translational Genomics Laboratory, University of Maryland School of Medicine

Mar 18, 2016

The c.278A>G variant in codon 93 (exon 3) of the insulin gene, INS, results in the substitution of Glutamic acid to Glycine. Missense variants in the INS gene are a common cause of permanent neonatal diabetes and a rare cause of a subtype of mature onset diabetes of the young (MODY) called MODY10 (17855560; 18192540; 18162506; 20226046; 25542748). The c.278A>G variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. In particular, the c.278A>G variant is in a highly-conserved residue located within the α-chain of the protein, and may be important for proper folding of the proinsulin molecule (18165206, 25542748). Additionally, there is little benign variation in this region among individuals in population databases and within the literature. ACMG Criteria = PM1, PM2, PP2, PP3 -

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

Uncertain risk allele, 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, as this mutation can cause beta cell destruction. However, no sufficient evidence is found to ascertain the role of this particular variant rs1057524907, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.2	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.20
MutPred		0.76		Gain of catalytic residue at C96 (P = 0.1247);Gain of catalytic residue at C96 (P = 0.1247);Gain of catalytic residue at C96 (P = 0.1247);.;
MVP		0.87
MPC		1.1
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1057524907; hg19: chr11-2181137;