chr11-2160994-A-T

Variant names:

• chr11-2160994-A-T
• rs689
• ENST00000397262.5:c.-23T>A

Variant summary

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

The NM_001042376.3(INS-IGF2):​c.-17-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,609,954 control chromosomes in the GnomAD database, including 415,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (32035 hom., cov: 35)
  • Exomes 𝑓: 0.72 (383950 hom.)
• Consequence: INS-IGF2 NM_001042376.3 splice_region, intron
• Scores: Splicing: ADA: 0.1228
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0740
• Publications: 236 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 11-2160994-A-T is Benign according to our data. Variant chr11-2160994-A-T is described in ClinVar as Benign. ClinVar VariationId is 304059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.-17-6T>A		splice_region intron	N/A	NP_000198.1
	INS	NM_001185098.2		c.-23T>A		5_prime_UTR	Exon 1 of 2	NP_001172027.1
	INS-IGF2	NM_001042376.3		c.-17-6T>A		splice_region intron	N/A	NP_001035835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000397262.5	TSL:1	c.-23T>A		5_prime_UTR	Exon 1 of 2	ENSP00000380432.1
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-17-6T>A		splice_region intron	N/A	ENSP00000370731.5
	INS-IGF2	ENST00000397270.1	TSL:1	c.-17-6T>A		splice_region intron	N/A	ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92830 AN: 152032 Hom.: 32028 Cov.: 35

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.669

GnomAD2 exomes AF: 0.734 AC: 178240 AN: 242726 AF XY: 0.745

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.953

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.720 AC: 1049977 AN: 1457804 Hom.: 383950 Cov.: 61 AF XY: 0.725 AC XY: 525501 AN XY: 725156

African (AFR) AF: 0.245 AC: 8177 AN: 33438

American (AMR) AF: 0.762 AC: 33884 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18395 AN: 26076

East Asian (EAS) AF: 0.959 AC: 38023 AN: 39664

South Asian (SAS) AF: 0.827 AC: 71293 AN: 86168

European-Finnish (FIN) AF: 0.792 AC: 40663 AN: 51324

Middle Eastern (MID) AF: 0.789 AC: 4293 AN: 5442

European-Non Finnish (NFE) AF: 0.713 AC: 792116 AN: 1110992

Other (OTH) AF: 0.716 AC: 43133 AN: 60230

GnomAD4 genome AF: 0.610 AC: 92854 AN: 152150 Hom.: 32035 Cov.: 35 AF XY: 0.624 AC XY: 46388 AN XY: 74386

African (AFR) AF: 0.263 AC: 10901 AN: 41518

American (AMR) AF: 0.725 AC: 11094 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3470

East Asian (EAS) AF: 0.948 AC: 4894 AN: 5164

South Asian (SAS) AF: 0.831 AC: 4010 AN: 4824

European-Finnish (FIN) AF: 0.792 AC: 8397 AN: 10602

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48839 AN: 67968

Other (OTH) AF: 0.673 AC: 1422 AN: 2112

Alfa AF: 0.676 Hom.: 6698

Bravo AF: 0.588

Asia WGS AF: 0.841 AC: 2925 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 10 (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	5.2
DANN	Benign	0.75
PhyloP100		-0.074
PromoterAI		0.018	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.38		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs689; hg19: chr11-2182224;