chr11-2159935-C-T

Position:

• chr11-2159935-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000207.3(INS):​c.250G>A​(p.Gly84Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.00500

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a disulfide_bond Interchain (between B and A chains) (size 65) in uniprot entity INS_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30279744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.250G>A	p.Gly84Arg	missense_variant	3/3	ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4	n.246+850G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.250G>A	p.Gly84Arg	missense_variant	3/3	1	NM_000207.3	ENSP00000370731	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes mellitus, permanent neonatal 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.G84R/ rs121908274 variant is Prevalent in patients with Permanent neonatal diabetes mellitus.However, the role of this particular variant is yet to be ascertained -

Permanent neonatal diabetes mellitus Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	9.8
DANN	Benign	0.93
DEOGEN2	Uncertain	0.47	T;T;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.72	.;.;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.92	L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-0.24	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.97	D;D;D;P
Vest4		0.52
MutPred		0.57		Loss of methylation at K88 (P = 0.1482);Loss of methylation at K88 (P = 0.1482);Loss of methylation at K88 (P = 0.1482);.;
MVP		1.0
MPC		1.1
ClinPred		0.22	T
GERP RS		-2.6
Varity_R		0.12
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908274; hg19: chr11-2181165;