rs748749585

Variant names:

• chr11-2161302-G-A
• rs748749585
• ENST00000729705.1:n.174+2388G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2161302-G-A
• chr11-2161302-G-C
• chr11-2161302-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000729705.1(ENSG00000295384):​n.174+2388G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000575 in 313,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -2.01
• Publications: 15 publications found

Genes affected

ENSG00000295384 (HGNC:):

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000729705.1. 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.-152C>T		upstream_gene	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-152C>T		upstream_gene	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.-178C>T		upstream_gene	N/A	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.174+2388G>A		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.225+2388G>A		intron	N/A
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-152C>T		upstream_gene	N/A	ENSP00000370731.5	P01308-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000682 AC: 11 AN: 161262 Hom.: 0 Cov.: 0 AF XY: 0.0000490 AC XY: 4 AN XY: 81584

African (AFR) AF: 0.00 AC: 0 AN: 6260

American (AMR) AF: 0.000140 AC: 1 AN: 7122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5886

East Asian (EAS) AF: 0.00 AC: 0 AN: 13088

South Asian (SAS) AF: 0.000100 AC: 1 AN: 10000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 800

European-Non Finnish (NFE) AF: 0.0000806 AC: 8 AN: 99244

Other (OTH) AF: 0.0000991 AC: 1 AN: 10094

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74252

African (AFR) AF: 0.0000483 AC: 2 AN: 41390

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	-	INS-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.97
DANN	Benign	0.86
PhyloP100		-2.0
PromoterAI		-0.018	Neutral

Splicing

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

Other links and lift over

dbSNP: rs748749585; hg19: chr11-2182532;