19-7167940-T-G

Variant names:

• chr19-7167940-T-G
• rs2860177
• NM_000208.4:c.1610+28A>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.1610+28A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,784 control chromosomes in the GnomAD database, including 49,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4518 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45477 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0650
• Publications: 12 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=-0.97).
• BP6: Variant 19-7167940-T-G is Benign according to our data. Variant chr19-7167940-T-G is described in ClinVar as Benign. ClinVar VariationId is 439831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.1610+28A>C		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.1610+28A>C		intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.1610+28A>C		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.1610+28A>C		intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.1585+28A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36686 AN: 151696 Hom.: 4508 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.259 AC: 64942 AN: 251092 AF XY: 0.260

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.247 AC: 361367 AN: 1460970 Hom.: 45477 Cov.: 34 AF XY: 0.248 AC XY: 180316 AN XY: 726788

African (AFR) AF: 0.206 AC: 6897 AN: 33454

American (AMR) AF: 0.258 AC: 11507 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8435 AN: 26116

East Asian (EAS) AF: 0.222 AC: 8789 AN: 39676

South Asian (SAS) AF: 0.263 AC: 22696 AN: 86236

European-Finnish (FIN) AF: 0.316 AC: 16875 AN: 53360

Middle Eastern (MID) AF: 0.305 AC: 1721 AN: 5646

European-Non Finnish (NFE) AF: 0.242 AC: 269162 AN: 1111462

Other (OTH) AF: 0.253 AC: 15285 AN: 60334

GnomAD4 genome AF: 0.242 AC: 36730 AN: 151814 Hom.: 4518 Cov.: 31 AF XY: 0.246 AC XY: 18269 AN XY: 74132

African (AFR) AF: 0.208 AC: 8605 AN: 41382

American (AMR) AF: 0.244 AC: 3709 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3466

East Asian (EAS) AF: 0.249 AC: 1285 AN: 5162

South Asian (SAS) AF: 0.266 AC: 1275 AN: 4796

European-Finnish (FIN) AF: 0.331 AC: 3484 AN: 10526

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16427 AN: 67948

Other (OTH) AF: 0.277 AC: 585 AN: 2110

Alfa AF: 0.249 Hom.: 1057

Bravo AF: 0.233

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Rabson-Mendenhall syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leprechaunism syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.25
DANN	Benign	0.25
PhyloP100		-0.065
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2860177; hg19: chr19-7167951; COSMIC: COSV57156805;