rs13306451

Variant names:

• chr19-7142813-T-C
• rs13306451
• NM_000208.4:c.2542+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-7142813-T-C
• chr19-7142813-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000208.4(INSR):​c.2542+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,613,910 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (50 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (114 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Scores: Splicing: ADA: 0.08482
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07
• Publications: 7 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):

• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• insulin-resistance syndrome type A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-7142813-T-C is Benign according to our data. Variant chr19-7142813-T-C is described in ClinVar as Benign. ClinVar VariationId is 330457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0184 (2807/152298) while in subpopulation AFR AF = 0.0437 (1817/41562). AF 95% confidence interval is 0.042. There are 50 homozygotes in GnomAd4. There are 1370 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.2542+3A>G		splice_region intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2506+3A>G		splice_region intron	N/A	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.2542+3A>G		splice_region intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2506+3A>G		splice_region intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.2542+3A>G		splice_region intron	N/A	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2791 AN: 152180 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0113 AC: 2815 AN: 249188 AF XY: 0.0100

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0393

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00964

GnomAD4 exome AF: 0.00834 AC: 12190 AN: 1461612 Hom.: 114 Cov.: 32 AF XY: 0.00794 AC XY: 5772 AN XY: 727112

African (AFR) AF: 0.0425 AC: 1422 AN: 33474

American (AMR) AF: 0.00465 AC: 208 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 339 AN: 26136

East Asian (EAS) AF: 0.0419 AC: 1662 AN: 39700

South Asian (SAS) AF: 0.00219 AC: 189 AN: 86244

European-Finnish (FIN) AF: 0.0105 AC: 559 AN: 53228

Middle Eastern (MID) AF: 0.00925 AC: 53 AN: 5730

European-Non Finnish (NFE) AF: 0.00639 AC: 7103 AN: 1111992

Other (OTH) AF: 0.0108 AC: 655 AN: 60384

GnomAD4 genome AF: 0.0184 AC: 2807 AN: 152298 Hom.: 50 Cov.: 31 AF XY: 0.0184 AC XY: 1370 AN XY: 74484

African (AFR) AF: 0.0437 AC: 1817 AN: 41562

American (AMR) AF: 0.00719 AC: 110 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0414 AC: 215 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00960 AC: 102 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00663 AC: 451 AN: 68004

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0126 Hom.: 14

Bravo AF: 0.0200

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00510

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	not provided (1)
-	-	1	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.77
PhyloP100		1.1
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.085
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.020		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: rs13306451; hg19: chr19-7142824;