NM_000208.4:c.653-7_653-6insTC

Variant names:

• chr19-7184643-G-GGA
• rs1555746860
• NM_000208.4:c.653-7_653-6insTC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000208.4(INSR):​c.653-7_653-6insTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.353
• Publications: 0 publications found

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-7184643-G-GGA is Benign according to our data. Variant chr19-7184643-G-GGA is described in ClinVar as Likely_benign. ClinVar VariationId is 435515.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.653-7_653-6insTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-7_653-6insTC		splice_region intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.653-7_653-6insTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-7_653-6insTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-7_628-6insTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 15, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35

Splicing

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

Other links and lift over

dbSNP: rs1555746860; hg19: chr19-7184654;