rs11564720

Variant names:

• chr11-2160909-T-C
• rs11564720
• NM_000207.3:c.63A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000207.3(INS):​c.63A>G​(p.Pro21Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,630 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 35)
  • Exomes 𝑓: 0.00070 (5 hom.)
• Consequence: INS NM_000207.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.88
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant 11-2160909-T-C is Benign according to our data. Variant chr11-2160909-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255533.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00504 (767/152308) while in subpopulation AFR AF = 0.0171 (709/41572). AF 95% confidence interval is 0.016. There are 6 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.63A>G	p.Pro21Pro	synonymous	Exon 2 of 3	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.63A>G	p.Pro21Pro	synonymous	Exon 2 of 5	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.63A>G	p.Pro21Pro	synonymous	Exon 2 of 3	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.63A>G	p.Pro21Pro	synonymous	Exon 2 of 3	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.63A>G	p.Pro21Pro	synonymous	Exon 2 of 5	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.63A>G	p.Pro21Pro	synonymous	Exon 2 of 3	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152190 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00148 AC: 366 AN: 247266 AF XY: 0.00123

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000698 AC: 1019 AN: 1460322 Hom.: 5 Cov.: 88 AF XY: 0.000640 AC XY: 465 AN XY: 726482

African (AFR) AF: 0.0173 AC: 579 AN: 33476

American (AMR) AF: 0.00130 AC: 58 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52122

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1111830

Other (OTH) AF: 0.00161 AC: 97 AN: 60352

GnomAD4 genome AF: 0.00504 AC: 767 AN: 152308 Hom.: 6 Cov.: 35 AF XY: 0.00470 AC XY: 350 AN XY: 74472

African (AFR) AF: 0.0171 AC: 709 AN: 41572

American (AMR) AF: 0.00183 AC: 28 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00254 Hom.: 1

Bravo AF: 0.00606

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	Maturity-onset diabetes of the young type 10 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.011
DANN	Benign	0.26
PhyloP100		-2.9
PromoterAI		0.0019	Neutral
Mutation Taster		=100/0	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: rs11564720; hg19: chr11-2182139;