GeneBe

NM_000208.4:c.1861+27C>G

Variant names:

Variant summary

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

The NM_000208.4(INSR):​c.1861+27C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INSR
NM_000208.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0550

Publications

18 publications found
Variant links:
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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INSRNM_000208.4 linkc.1861+27C>G intron_variant Intron 8 of 21 ENST00000302850.10 NP_000199.2 P06213-1
INSRNM_001079817.3 linkc.1861+27C>G intron_variant Intron 8 of 20 NP_001073285.1 P06213-2
INSRXM_011527988.3 linkc.1861+27C>G intron_variant Intron 8 of 21 XP_011526290.2
INSRXM_011527989.4 linkc.1861+27C>G intron_variant Intron 8 of 20 XP_011526291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INSRENST00000302850.10 linkc.1861+27C>G intron_variant Intron 8 of 21 1 NM_000208.4 ENSP00000303830.4 P06213-1
INSRENST00000341500.9 linkc.1861+27C>G intron_variant Intron 8 of 20 1 ENSP00000342838.4 P06213-2
INSRENST00000598216.1 linkn.1836+27C>G intron_variant Intron 8 of 9 1
INSRENST00000600492.1 linkc.262+27C>G intron_variant Intron 2 of 3 5 ENSP00000473170.1 M0R3E6

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461018
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
726864
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33460
American (AMR)
AF:
0.00
AC:
0
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39658
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86150
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53376
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111432
Other (OTH)
AF:
0.00
AC:
0
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00
Hom.:
2774
Bravo
AF:
0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
18
DANN
Benign
0.46
PhyloP100
-0.055

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.48
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.48
Position offset: 0

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

Publications

Other links and lift over

dbSNP: rs3815902; hg19: chr19-7166138; API