11-2160828-GA-AC

Variant names:

• chr11-2160828-GA-AC
• NM_000207.3:c.143_144delTCinsGT
• INS p.Phe48Cys

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1_Very_Strong PM1 PM5 PP2

The NM_000207.3(INS):​c.143_144delTCinsGT​(p.Phe48Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F48S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11
• Publications: 0 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 13 ACMG points.

• PS1: Transcript NM_000207.3 (INS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000207.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2160829-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13378.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.

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.143_144delTCinsGT	p.Phe48Cys	missense	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.143_144delTCinsGT	p.Phe48Cys	missense	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.143_144delTCinsGT	p.Phe48Cys	missense	N/A	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.143_144delTCinsGT	p.Phe48Cys	missense	N/A	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.143_144delTCinsGT	p.Phe48Cys	missense	N/A	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.143_144delTCinsGT	p.Phe48Cys	missense	N/A	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes Cov.: 35

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-2182058;