rs2252673

Variant names:

• chr19-7150407-C-G
• rs2252673
• NM_000208.4:c.2267+90G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.2267+90G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,251,622 control chromosomes in the GnomAD database, including 392,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42976 hom., cov: 34)
  • Exomes 𝑓: 0.79 (349337 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.462
• Publications: 35 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7150407-C-G is Benign according to our data. Variant chr19-7150407-C-G is described in ClinVar as Benign. ClinVar VariationId is 1246658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2267+90G>C		intron_variant	Intron 11 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2231+2319G>C		intron_variant	Intron 10 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2267+90G>C		intron_variant	Intron 11 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2231+2319G>C		intron_variant	Intron 10 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2267+90G>C		intron_variant	Intron 11 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2231+2319G>C		intron_variant	Intron 10 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113081 AN: 152056 Hom.: 42953 Cov.: 34

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.774

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.789 AC: 867898 AN: 1099446 Hom.: 349337 AF XY: 0.791 AC XY: 443326 AN XY: 560728

African (AFR) AF: 0.684 AC: 18010 AN: 26312

American (AMR) AF: 0.596 AC: 23958 AN: 40218

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 16991 AN: 23416

East Asian (EAS) AF: 0.292 AC: 11028 AN: 37704

South Asian (SAS) AF: 0.773 AC: 59053 AN: 76382

European-Finnish (FIN) AF: 0.786 AC: 39095 AN: 49718

Middle Eastern (MID) AF: 0.740 AC: 2944 AN: 3976

European-Non Finnish (NFE) AF: 0.832 AC: 659943 AN: 793322

Other (OTH) AF: 0.762 AC: 36876 AN: 48398

GnomAD4 genome AF: 0.744 AC: 113143 AN: 152176 Hom.: 42976 Cov.: 34 AF XY: 0.736 AC XY: 54743 AN XY: 74372

African (AFR) AF: 0.683 AC: 28333 AN: 41512

American (AMR) AF: 0.657 AC: 10040 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2550 AN: 3472

East Asian (EAS) AF: 0.344 AC: 1786 AN: 5186

South Asian (SAS) AF: 0.764 AC: 3679 AN: 4818

European-Finnish (FIN) AF: 0.782 AC: 8278 AN: 10592

Middle Eastern (MID) AF: 0.781 AC: 228 AN: 292

European-Non Finnish (NFE) AF: 0.823 AC: 55995 AN: 68004

Other (OTH) AF: 0.746 AC: 1577 AN: 2114

Alfa AF: 0.778 Hom.: 5758

Bravo AF: 0.728

Asia WGS AF: 0.609 AC: 2121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs2252673; hg19: chr19-7150418; COSMIC: COSV57173311; COSMIC: COSV57173311;