rs121913143
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_000208.4(INSR):c.126C>A(p.Asn42Lys) 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 31)
Consequence
INSR
NM_000208.4 missense
NM_000208.4 missense
Scores
3
12
3
Clinical Significance
Conservation
PhyloP100: 1.97
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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, INSR
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
?
Variant 19-7267871-G-T is Pathogenic according to our data. Variant chr19-7267871-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14691.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INSR | NM_000208.4 | c.126C>A | p.Asn42Lys | missense_variant | 2/22 | ENST00000302850.10 | |
INSR | NM_001079817.3 | c.126C>A | p.Asn42Lys | missense_variant | 2/21 | ||
INSR | XM_011527988.3 | c.126C>A | p.Asn42Lys | missense_variant | 2/22 | ||
INSR | XM_011527989.4 | c.126C>A | p.Asn42Lys | missense_variant | 2/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INSR | ENST00000302850.10 | c.126C>A | p.Asn42Lys | missense_variant | 2/22 | 1 | NM_000208.4 | A2 | |
INSR | ENST00000341500.9 | c.126C>A | p.Asn42Lys | missense_variant | 2/21 | 1 | P3 | ||
INSR | ENST00000598216.1 | n.101C>A | non_coding_transcript_exon_variant | 2/10 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Rabson-Mendenhall syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 05, 1990 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of ubiquitination at N42 (P = 0.0247);Gain of ubiquitination at N42 (P = 0.0247);
MVP
MPC
2.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at