chr11-2160980-G-A

Variant names:

• chr11-2160980-G-A
• rs5505
• NM_000207.3:c.-9C>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.-9C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,611,934 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 35)
  • Exomes 𝑓: 0.012 (120 hom.)
• Consequence: INS NM_000207.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.13
• Publications: 21 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=-0.84).
• BP6: Variant 11-2160980-G-A is Benign according to our data. Variant chr11-2160980-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00872 (1329/152330) while in subpopulation NFE AF = 0.0124 (843/68012). AF 95% confidence interval is 0.0117. There are 11 homozygotes in GnomAd4. There are 708 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.-9C>T		5_prime_UTR	Exon 2 of 3	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-9C>T		5_prime_UTR	Exon 2 of 5	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.-9C>T		5_prime_UTR	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.-9C>T		5_prime_UTR	Exon 2 of 3	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.-9C>T		5_prime_UTR	Exon 2 of 5	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.-9C>T		5_prime_UTR	Exon 2 of 3	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1332 AN: 152212 Hom.: 11 Cov.: 35

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00862 AC: 2115 AN: 245352 AF XY: 0.00899

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.000906

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0118 AC: 17187 AN: 1459604 Hom.: 120 Cov.: 88 AF XY: 0.0116 AC XY: 8415 AN XY: 726120

African (AFR) AF: 0.00176 AC: 59 AN: 33466

American (AMR) AF: 0.00481 AC: 215 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26100

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00673 AC: 580 AN: 86214

European-Finnish (FIN) AF: 0.0235 AC: 1218 AN: 51778

Middle Eastern (MID) AF: 0.00317 AC: 18 AN: 5674

European-Non Finnish (NFE) AF: 0.0130 AC: 14427 AN: 1111680

Other (OTH) AF: 0.0106 AC: 640 AN: 60326

GnomAD4 genome AF: 0.00872 AC: 1329 AN: 152330 Hom.: 11 Cov.: 35 AF XY: 0.00950 AC XY: 708 AN XY: 74492

African (AFR) AF: 0.00204 AC: 85 AN: 41582

American (AMR) AF: 0.00555 AC: 85 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.0251 AC: 267 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0124 AC: 843 AN: 68012

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00910 Hom.: 7

Bravo AF: 0.00652

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	-	1	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	Neonatal diabetes mellitus (1)
-	-	1	not specified (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.43
DANN	Benign	0.55
PhyloP100		-1.1
PromoterAI		0.0026	Neutral
Mutation Taster		=291/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5505; hg19: chr11-2182210;