chr11-2160774-A-G

Variant names:

• chr11-2160774-A-G
• rs5506
• NM_000207.3:c.187+11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000207.3(INS):​c.187+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,610,624 control chromosomes in the GnomAD database, including 787,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67638 hom., cov: 35)
  • Exomes 𝑓: 0.99 (720155 hom.)
• Consequence: INS NM_000207.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.166
• Publications: 22 publications found

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2160774-A-G is Benign according to our data. Variant chr11-2160774-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. 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
	INS	NM_000207.3	MANE Select	c.187+11T>C		intron	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.187+11T>C		intron	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.187+11T>C		intron	N/A	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.187+11T>C		intron	N/A	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.187+11T>C		intron	N/A	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.187+11T>C		intron	N/A	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142735 AN: 152154 Hom.: 67600 Cov.: 35

Gnomad AFR AF: 0.784

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.956

GnomAD2 exomes AF: 0.984 AC: 242627 AN: 246646 AF XY: 0.988

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.993 AC: 1448313 AN: 1458352 Hom.: 720155 Cov.: 62 AF XY: 0.994 AC XY: 720715 AN XY: 725112

African (AFR) AF: 0.763 AC: 25496 AN: 33434

American (AMR) AF: 0.988 AC: 44141 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26040 AN: 26088

East Asian (EAS) AF: 1.00 AC: 39616 AN: 39618

South Asian (SAS) AF: 0.999 AC: 86166 AN: 86218

European-Finnish (FIN) AF: 1.00 AC: 52110 AN: 52110

Middle Eastern (MID) AF: 0.990 AC: 5686 AN: 5744

European-Non Finnish (NFE) AF: 1.00 AC: 1109691 AN: 1110212

Other (OTH) AF: 0.985 AC: 59367 AN: 60256

GnomAD4 genome AF: 0.938 AC: 142824 AN: 152272 Hom.: 67638 Cov.: 35 AF XY: 0.940 AC XY: 70000 AN XY: 74448

African (AFR) AF: 0.784 AC: 32556 AN: 41534

American (AMR) AF: 0.979 AC: 14993 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3466 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5156 AN: 5158

South Asian (SAS) AF: 0.999 AC: 4829 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67978 AN: 68022

Other (OTH) AF: 0.956 AC: 2020 AN: 2114

Alfa AF: 0.969 Hom.: 29615

Bravo AF: 0.929

Asia WGS AF: 0.988 AC: 3436 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	-	1	Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 (1)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Maturity-onset diabetes of the young type 10 (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.10
DANN	Benign	0.52
PhyloP100		-0.17
PromoterAI		0.0038	Neutral
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: rs5506; hg19: chr11-2182004;