rs5507

Variant names:

• chr11-2160013-G-A
• rs5507
• NM_000207.3:c.188-16C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2160013-G-A
• chr11-2160013-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000207.3(INS):​c.188-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,571,286 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (10 hom.)
• Consequence: INS NM_000207.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.12
• Publications: 7 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=-0.94).
• BP6: Variant 11-2160013-G-A is Benign according to our data. Variant chr11-2160013-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36400.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 = 0.00587 (894/152298) while in subpopulation AFR AF = 0.0197 (819/41574). AF 95% confidence interval is 0.0186. There are 12 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.188-16C>T		intron	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.187+772C>T		intron	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.188-16C>T		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.188-16C>T		intron	N/A	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.187+772C>T		intron	N/A	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.188-16C>T		intron	N/A	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152180 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00130 AC: 238 AN: 183460 AF XY: 0.000993

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000660

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000140

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.000406

GnomAD4 exome AF: 0.000662 AC: 939 AN: 1418988 Hom.: 10 Cov.: 35 AF XY: 0.000596 AC XY: 419 AN XY: 702736

African (AFR) AF: 0.0210 AC: 693 AN: 33016

American (AMR) AF: 0.00140 AC: 54 AN: 38680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38268

South Asian (SAS) AF: 0.0000491 AC: 4 AN: 81482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42886

Middle Eastern (MID) AF: 0.000209 AC: 1 AN: 4794

European-Non Finnish (NFE) AF: 0.000101 AC: 111 AN: 1095420

Other (OTH) AF: 0.00127 AC: 75 AN: 58994

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152298 Hom.: 12 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74480

African (AFR) AF: 0.0197 AC: 819 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68008

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00697

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	Neonatal diabetes mellitus (1)
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.77
DANN	Benign	0.65
PhyloP100		-2.1
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: rs5507; hg19: chr11-2181243;