chr19-7126626-G-T

Variant names:

• chr19-7126626-G-T
• rs150114699
• NM_000208.4:c.2971C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000208.4(INSR):​c.2971C>A​(p.Leu991Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,565,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.60
• Publications: 6 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 -15 ACMG points.

• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015149355).
• BP6: Variant 19-7126626-G-T is Benign according to our data. Variant chr19-7126626-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211196.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 = 0.00275 (419/152284) while in subpopulation AFR AF = 0.00953 (396/41552). AF 95% confidence interval is 0.00876. There are 0 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2971C>A	p.Leu991Ile	missense	Exon 16 of 22	NP_000199.2
	INSR	NM_001079817.3		c.2935C>A	p.Leu979Ile	missense	Exon 15 of 21	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.2971C>A	p.Leu991Ile	missense	Exon 16 of 22	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.2935C>A	p.Leu979Ile	missense	Exon 15 of 21	ENSP00000342838.4
	INSR	ENST00000904791.1		c.2968C>A	p.Leu990Ile	missense	Exon 16 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00956

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000485 AC: 86 AN: 177380 AF XY: 0.000435

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000277 AC: 391 AN: 1413226 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 161 AN XY: 698178

African (AFR) AF: 0.00956 AC: 311 AN: 32546

American (AMR) AF: 0.000582 AC: 22 AN: 37774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25400

East Asian (EAS) AF: 0.00 AC: 0 AN: 37544

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50104

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1085302

Other (OTH) AF: 0.000735 AC: 43 AN: 58498

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74468

African (AFR) AF: 0.00953 AC: 396 AN: 41552

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00115 Hom.: 2

Bravo AF: 0.00319

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00659 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000454 AC: 53

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperinsulinism due to INSR deficiency (1)
-	-	1	INSR-related disorder (1)
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Monogenic diabetes (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.1
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.046	D
Sift4G	Benign	0.080	T
Polyphen		0.58	P
Vest4		0.21
MVP		0.81
MPC		1.1
ClinPred		0.027	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.45
Mutation Taster		=72/28	polymorphism

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: rs150114699; hg19: chr19-7126637;