chr19-7293887-G-C

Variant names:

• chr19-7293887-G-C
• rs7508518
• NM_000208.4:c.5C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 151,276 control chromosomes in the GnomAD database, including 75,632 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75632 hom., cov: 31)
  • Exomes 𝑓: 1.0 (538310 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.458
• Publications: 29 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

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

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

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

ACMG classification

Our verdict: Benign. The variant received -19 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=1.1230504E-6).
• BP6: Variant 19-7293887-G-C is Benign according to our data. Variant chr19-7293887-G-C is described in ClinVar as Benign. ClinVar VariationId is 193063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.5C>G	p.Ala2Gly	missense	Exon 1 of 21	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.5C>G	p.Ala2Gly	missense	Exon 1 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.5C>G	p.Ala2Gly	missense	Exon 1 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 1.00 AC: 151160 AN: 151166 Hom.: 75577 Cov.: 31

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.999

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 332 AN: 332 AF XY: 1.00

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 1.00 AC: 1076634 AN: 1076648 Hom.: 538310 Cov.: 34 AF XY: 1.00 AC XY: 515857 AN XY: 515860

African (AFR) AF: 1.00 AC: 21530 AN: 21530

American (AMR) AF: 1.00 AC: 7149 AN: 7150

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 12582 AN: 12582

East Asian (EAS) AF: 1.00 AC: 23099 AN: 23108

South Asian (SAS) AF: 1.00 AC: 23634 AN: 23634

European-Finnish (FIN) AF: 1.00 AC: 20701 AN: 20702

Middle Eastern (MID) AF: 1.00 AC: 2770 AN: 2770

European-Non Finnish (NFE) AF: 1.00 AC: 922958 AN: 922960

Other (OTH) AF: 1.00 AC: 42211 AN: 42212

GnomAD4 genome AF: 1.00 AC: 151270 AN: 151276 Hom.: 75632 Cov.: 31 AF XY: 1.00 AC XY: 73953 AN XY: 73958

African (AFR) AF: 1.00 AC: 41422 AN: 41422

American (AMR) AF: 1.00 AC: 15183 AN: 15184

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3466 AN: 3466

East Asian (EAS) AF: 0.999 AC: 5081 AN: 5086

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10248 AN: 10248

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67740 AN: 67740

Other (OTH) AF: 1.00 AC: 2098 AN: 2098

Alfa AF: 1.00 Hom.: 9259

Bravo AF: 1.00

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ExAC AF: 1.00 AC: 1674

Asia WGS AF: 1.00 AC: 3240 AN: 3240

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Insulin-resistant diabetes mellitus AND acanthosis nigricans (2)
-	-	2	Leprechaunism syndrome (2)
-	-	2	Rabson-Mendenhall syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.46
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.46
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.47	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.76
ClinPred		0.0043	T
GERP RS		2.6
PromoterAI		-0.27	Neutral
Varity_R		0.029
gMVP		0.55
Mutation Taster		=98/2	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: rs7508518; hg19: chr19-7293898; COSMIC: COSV105137469; COSMIC: COSV105137469;