ENST00000598216.1:n.2240G>A

Variant names:

• chr19-7152692-C-T
• rs3745548
• ENST00000598216.1:n.2240G>A

Variant summary

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

The ENST00000598216.1(INSR):​n.2240G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,571,264 control chromosomes in the GnomAD database, including 7,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (882 hom., cov: 31)
  • Exomes 𝑓: 0.030 (6976 hom.)
• Consequence: INSR ENST00000598216.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.403
• Publications: 10 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=-0.82).
• BP6: Variant 19-7152692-C-T is Benign according to our data. Variant chr19-7152692-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2231+34G>A		intron_variant	Intron 10 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2231+34G>A		intron_variant	Intron 10 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2231+34G>A		intron_variant	Intron 10 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2231+34G>A		intron_variant	Intron 10 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000598216.1	n.2240G>A		non_coding_transcript_exon_variant	Exon 10 of 10	1
INSR	ENST00000302850.10	c.2231+34G>A		intron_variant	Intron 10 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2231+34G>A		intron_variant	Intron 10 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6499 AN: 151976 Hom.: 878 Cov.: 31

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.0558

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0837 AC: 20858 AN: 249218 AF XY: 0.0725

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.00785

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0299 AC: 42399 AN: 1419170 Hom.: 6976 Cov.: 26 AF XY: 0.0288 AC XY: 20411 AN XY: 708250

African (AFR) AF: 0.00316 AC: 103 AN: 32612

American (AMR) AF: 0.224 AC: 9994 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00861 AC: 223 AN: 25900

East Asian (EAS) AF: 0.515 AC: 20308 AN: 39464

South Asian (SAS) AF: 0.0405 AC: 3455 AN: 85250

European-Finnish (FIN) AF: 0.0561 AC: 2984 AN: 53204

Middle Eastern (MID) AF: 0.00526 AC: 22 AN: 4184

European-Non Finnish (NFE) AF: 0.00264 AC: 2835 AN: 1075000

Other (OTH) AF: 0.0420 AC: 2475 AN: 58900

GnomAD4 genome AF: 0.0428 AC: 6509 AN: 152094 Hom.: 882 Cov.: 31 AF XY: 0.0509 AC XY: 3784 AN XY: 74334

African (AFR) AF: 0.00496 AC: 206 AN: 41522

American (AMR) AF: 0.167 AC: 2551 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.488 AC: 2498 AN: 5118

South Asian (SAS) AF: 0.0550 AC: 265 AN: 4814

European-Finnish (FIN) AF: 0.0602 AC: 638 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68000

Other (OTH) AF: 0.0322 AC: 68 AN: 2110

Alfa AF: 0.0222 Hom.: 214

Bravo AF: 0.0521

Asia WGS AF: 0.219 AC: 758 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.78
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3745548; hg19: chr19-7152703; COSMIC: COSV57164517;