11-2159895-G-C

Position:

• chr11-2159895-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000207.3(INS):​c.290C>G​(p.Thr97Ser) 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 benign 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. T97P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 O:1
• Conservation: PhyloP100: 1.96

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr11-2159896-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1336487.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-2159895-G-C is Pathogenic according to our data. Variant chr11-2159895-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 617648.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_risk_allele=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21943894). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.290C>G	p.Thr97Ser	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+890C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.290C>G	p.Thr97Ser	missense_variant	3/3	1	NM_000207.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Translational Genomics Laboratory, University of Maryland School of Medicine

Sep 07, 2017

The c.290C>G variant in codon 97 (exon 3) of the insulin gene, INS, results in the substitution of Threonine to Serine. 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.290C>G variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (FATHMM, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. In particular, the c.290C>G variant is located within the alpha-chain of the protein, and may be important for proper folding of the proinsulin molecule (18162506). Additionally, there is little benign variation in this region among individuals in population databases and within the literature. ACMG criteria = PM1, PM2, PP2, PP3 -

Neonatal insulin-dependent diabetes mellitus Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in 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 rs1564911425, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Uncertain	0.54	D;D;D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.35	.;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.62	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.12	B;B;B;B
Vest4		0.14
MutPred		0.55		Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);.;
MVP		0.83
MPC		0.39
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.54
gMVP		0.61

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: rs1564911425; hg19: chr11-2181125;