rs1554920552

Variant names:

• chr11-2159859-CAGT-C
• rs1554920552
• NM_000207.3:c.323_325delACT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PM4_Supporting BP6

The NM_000207.3(INS):​c.323_325delACT​(p.Tyr108del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INS NM_000207.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.42
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000207.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 11-2159859-CAGT-C is Benign according to our data. Variant chr11-2159859-CAGT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435510.

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.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	Exon 3 of 3	NP_000198.1	P01308-1
	INS	NM_001185097.2		c.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	Exon 3 of 3	NP_001172026.1	I3WAC9
	INS	NM_001185098.2		c.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	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.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000370731.5	P01308-1
	INS	ENST00000250971.7	TSL:1	c.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000250971.3	P01308-1
	INS	ENST00000397262.5	TSL:1	c.323_325delACT	p.Tyr108del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000380432.1	P01308-1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

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: rs1554920552; hg19: chr11-2181089;