11-2159919-C-G

Variant names:

• chr11-2159919-C-G
• rs28933985
• NM_000207.3:c.266G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1 PM2 PM5 PP3_Strong PP5 BS2_Supporting

The NM_000207.3(INS):​c.266G>C​(p.Arg89Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,451,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.33

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:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2159920-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 11-2159919-C-G is Pathogenic according to our data. Variant chr11-2159919-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13383.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.266G>C	p.Arg89Pro	missense_variant	Exon 3 of 3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.266G>C	p.Arg89Pro	missense_variant	Exon 3 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.187+866G>C		intron_variant	Intron 2 of 4	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451498 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperproinsulinemia Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;D;.
Eigen	Benign	0.028
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	.;.;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.6	M;M;M;.
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.036	D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;D
Polyphen		1.0	D;D;D;B
Vest4		0.91
MutPred		0.86		Gain of catalytic residue at R89 (P = 0.048);Gain of catalytic residue at R89 (P = 0.048);Gain of catalytic residue at R89 (P = 0.048);.;
MVP		1.0
MPC		1.4
ClinPred		0.96	D
GERP RS		2.7
Varity_R		0.96
gMVP		0.99

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: rs28933985; hg19: chr11-2181149;