rs1252051752

chr11-2159893-T-Achr11-2159893-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000207.3(INS):c.292A>T(p.Ser98Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S98I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:1 O:1
• Conservation: PhyloP100: 0.791

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, 7 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 chr11-2159892-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1526009.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.292A>T	p.Ser98Cys	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+892A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.292A>T	p.Ser98Cys	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/Uncertain risk allele

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 22, 2016

- -

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 rs1252051752, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;D;D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.026	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.28
MutPred		0.43		Loss of catalytic residue at S98 (P = 0.1871);Loss of catalytic residue at S98 (P = 0.1871);Loss of catalytic residue at S98 (P = 0.1871);.;
MVP		0.89
MPC		1.1
ClinPred		0.97	D
GERP RS		-0.17
Varity_R		0.85
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1252051752; hg19: chr11-2181123;