rs41352749
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_000208.4(INSR):c.225C>T(p.Asp75Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.000103 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
INSR
NM_000208.4 synonymous
NM_000208.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.96
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 19-7267772-G-A is Benign according to our data. Variant chr19-7267772-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000102 (149/1461876) while in subpopulation AMR AF= 0.00038 (17/44722). AF 95% confidence interval is 0.000242. There are 0 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| INSR | NM_000208.4 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/22 | ENST00000302850.10 | NP_000199.2 | |
| INSR | NM_001079817.3 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/21 | NP_001073285.1 | ||
| INSR | XM_011527988.3 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/22 | XP_011526290.2 | ||
| INSR | XM_011527989.4 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/21 | XP_011526291.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| INSR | ENST00000302850.10 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/22 | 1 | NM_000208.4 | ENSP00000303830.4 | ||
| INSR | ENST00000341500.9 | c.225C>T | p.Asp75Asp | synonymous_variant | 2/21 | 1 | ENSP00000342838.4 | |||
| INSR | ENST00000598216.1 | n.200C>T | non_coding_transcript_exon_variant | 2/10 | 1 |
Frequencies
GnomAD3 genomes 0.000112 AC: 17AN: 152156Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251370Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135856
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GnomAD4 exome AF: 0.000102 AC: 149AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.000100 AC XY: 73AN XY: 727244
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GnomAD4 genome 0.000112 AC: 17AN: 152156Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Insulin-resistant diabetes mellitus AND acanthosis nigricans Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Rabson-Mendenhall syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Leprechaunism syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 01, 2016 | - - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 20, 2023 | - - |
Hyperinsulinism due to INSR deficiency Benign:1
| Likely benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in INSR gene can lead to insulin resistance, which presents as impaired glucose tolerance, early onset type 2 diabetes, post prandial hyperglycemia and increased insulin requirement in type 1 diabetes. These mutations in INSR gene can also predispose to coronary artery disease, metabolic syndrome, polycystic ovarian disease and non alcoholic fatty liver disease.However, the role of this particular variant rs41352749 with early onset diabetes mellitus is yet to be ascertained. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at