rs6510959

Variant names:

• chr19-7184227-G-A
• rs6510959
• NM_000208.4:c.974+89C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7184227-G-A
• chr19-7184227-G-T

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.974+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,174,158 control chromosomes in the GnomAD database, including 20,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3267 hom., cov: 29)
  • Exomes 𝑓: 0.18 (17177 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.756
• 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=-0.8).
• BP6: Variant 19-7184227-G-A is Benign according to our data. Variant chr19-7184227-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.974+89C>T		intron_variant	Intron 3 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.974+89C>T		intron_variant	Intron 3 of 20		NP_001073285.1
INSR	XM_011527988.3	c.974+89C>T		intron_variant	Intron 3 of 21		XP_011526290.2
INSR	XM_011527989.4	c.974+89C>T		intron_variant	Intron 3 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.974+89C>T		intron_variant	Intron 3 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.974+89C>T		intron_variant	Intron 3 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.949+89C>T		intron_variant	Intron 3 of 9	1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30745 AN: 151476 Hom.: 3252 Cov.: 29

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.179 AC: 183441 AN: 1022564 Hom.: 17177 AF XY: 0.180 AC XY: 93734 AN XY: 520676

African (AFR) AF: 0.261 AC: 6498 AN: 24928

American (AMR) AF: 0.233 AC: 8808 AN: 37814

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 4483 AN: 22834

East Asian (EAS) AF: 0.128 AC: 4641 AN: 36382

South Asian (SAS) AF: 0.219 AC: 16082 AN: 73482

European-Finnish (FIN) AF: 0.204 AC: 8831 AN: 43376

Middle Eastern (MID) AF: 0.174 AC: 590 AN: 3396

European-Non Finnish (NFE) AF: 0.170 AC: 125032 AN: 734596

Other (OTH) AF: 0.185 AC: 8476 AN: 45756

GnomAD4 genome AF: 0.203 AC: 30803 AN: 151594 Hom.: 3267 Cov.: 29 AF XY: 0.206 AC XY: 15233 AN XY: 74044

African (AFR) AF: 0.258 AC: 10663 AN: 41302

American (AMR) AF: 0.211 AC: 3209 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3468

East Asian (EAS) AF: 0.118 AC: 610 AN: 5164

South Asian (SAS) AF: 0.219 AC: 1054 AN: 4806

European-Finnish (FIN) AF: 0.217 AC: 2276 AN: 10468

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11709 AN: 67900

Other (OTH) AF: 0.219 AC: 459 AN: 2096

Alfa AF: 0.192 Hom.: 386

Bravo AF: 0.205

Asia WGS AF: 0.188 AC: 653 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	-0.80
CADD	Benign	0.061
DANN	Benign	0.86
PhyloP100		-0.76
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: rs6510959; hg19: chr19-7184238; COSMIC: COSV57169425;