rs121908261

Variant names:

• chr11-2160809-G-A
• rs121908261
• NM_000207.3:c.163C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000207.3(INS):​c.163C>T​(p.Arg55Cys) 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 risk allele (★★). ClinVar reports functional evidence for this variant: "SCV001780921: Published functional studies demonstrate that R55C leads to the reduction of proinsulin secretion from the ER and potential activation of the ER stress response (Meur 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. R55H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.08
• Publications: 22 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001780921: Published functional studies demonstrate that R55C leads to the reduction of proinsulin secretion from the ER and potential activation of the ER stress response (Meur et al., 2010; Liu et al., 2010); SCV002257078: Experimental studies have shown that this missense change affects INS function (PMID: 20007936, 20948967).; SCV004803864: At least one publication reports experimental evidence that R55C leads to the reduction of proinsulin secretion from the ER (Meur_2010).; SCV005343185: In vitro functional studies demonstrate reduced proinsulin secretion, ER retention, and ER stress (Meur et al. 2009. PubMed ID: 20007936).
• PM1: In a hotspot region, there are 5 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
• 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, 0.926
• PP5: Variant 11-2160809-G-A is Pathogenic according to our data. Variant chr11-2160809-G-A is described in ClinVar as Pathogenic/Likely_pathogenic/Likely_risk_allele. ClinVar VariationId is 13392.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.163C>T	p.Arg55Cys	missense	Exon 2 of 3	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.163C>T	p.Arg55Cys	missense	Exon 2 of 5	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.163C>T	p.Arg55Cys	missense	Exon 2 of 3	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.163C>T	p.Arg55Cys	missense	Exon 2 of 3	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.163C>T	p.Arg55Cys	missense	Exon 2 of 5	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.163C>T	p.Arg55Cys	missense	Exon 2 of 3	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247468 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic/Likely risk allele

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	INS-related disorder (1)
1	-	-	Monogenic diabetes (1)
1	-	-	Type 1 diabetes mellitus 2 (2)
-	-	-	Diabetes mellitus type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.1
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.71		Loss of disorder (P = 0.0143)
MVP		0.91
MPC		1.0
ClinPred		0.98	D
GERP RS		3.1
PromoterAI		0.0024	Neutral
Varity_R		0.82
gMVP		0.88
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: rs121908261; hg19: chr11-2182039;