rs80356669

Variant names:

• chr11-2159920-G-A
• rs80356669
• NM_000207.3:c.265C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2159920-G-A
• chr11-2159920-G-C

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000207.3(INS):​c.265C>T​(p.Arg89Cys) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003837169: Published in vitro functional studies suggest a negative effect on subcellular insulin localization and incomplete processing of proinsulin to insulin, but no inhibition of wildtype insulin secretion (Rajan et al., 2010)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:2
• Conservation: PhyloP100: 0.612
• Publications: 30 publications found

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003837169: Published in vitro functional studies suggest a negative effect on subcellular insulin localization and incomplete processing of proinsulin to insulin, but no inhibition of wildtype insulin secretion (Rajan et al., 2010); SCV005340022: In vitro studies demonstrate that expression of this variant results in aberrant processing of proinsulin to insulin and retainment in the endoplasmic reticulum (Rajan et al. 2009. PubMed ID: 19952343; Park et al. 2009. PubMed ID: 20034470).
• 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 chr11-2159919-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13383.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.9004 (below the threshold of 3.09). Trascript score misZ: 0.85584 (below the threshold of 3.09). GenCC associations: The gene is linked to diabetes mellitus, permanent neonatal 4, monogenic diabetes, hyperproinsulinemia, maturity-onset diabetes of the young type 10, type 1 diabetes mellitus 2, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young, transient neonatal diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 11-2159920-G-A is Pathogenic according to our data. Variant chr11-2159920-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 3 of 3	NP_000198.1	P01308-1
	INS	NM_001185097.2		c.265C>T	p.Arg89Cys	missense	Exon 3 of 3	NP_001172026.1	I3WAC9
	INS	NM_001185098.2		c.265C>T	p.Arg89Cys	missense	Exon 2 of 2	NP_001172027.1	P01308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 3 of 3	ENSP00000370731.5	P01308-1
	INS	ENST00000250971.7	TSL:1	c.265C>T	p.Arg89Cys	missense	Exon 3 of 3	ENSP00000250971.3	P01308-1
	INS	ENST00000397262.5	TSL:1	c.265C>T	p.Arg89Cys	missense	Exon 2 of 2	ENSP00000380432.1	P01308-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450698 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720482

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 43064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 83972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107954

Other (OTH) AF: 0.00 AC: 0 AN: 60010

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000115 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Diabetes mellitus, permanent neonatal 4 (2)
2	-	-	not provided (2)
1	-	-	INS-related disorder (1)
1	-	-	Neonatal diabetes mellitus (1)
1	-	-	Permanent neonatal diabetes mellitus (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		0.61
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.81		Gain of methylation at K88 (P = 0.0249)
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.89
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356669; hg19: chr11-2181150;