chr11-2161106-G-T

Variant names:

• chr11-2161106-G-T
• rs1166335966
• ENST00000397262.5:c.-135C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001291897.2(INS):​c.-18+2C>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000174 in 1,150,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: INS NM_001291897.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.419
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3063063 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291897.2. 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.-18+62C>A		intron	N/A	NP_000198.1	P01308-1
	INS	NM_001185098.2		c.-135C>A		5_prime_UTR	Exon 1 of 2	NP_001172027.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-18+62C>A		intron	N/A	NP_001035835.1	F8WCM5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000397262.5	TSL:1	c.-135C>A		5_prime_UTR	Exon 1 of 2	ENSP00000380432.1	P01308-1
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-18+62C>A		intron	N/A	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.-18+62C>A		intron	N/A	ENSP00000380440.1	F8WCM5-1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000174 AC: 2 AN: 1150188 Hom.: 0 Cov.: 17 AF XY: 0.00000353 AC XY: 2 AN XY: 566110

African (AFR) AF: 0.00 AC: 0 AN: 25818

American (AMR) AF: 0.00 AC: 0 AN: 26806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19636

East Asian (EAS) AF: 0.00 AC: 0 AN: 34312

South Asian (SAS) AF: 0.0000311 AC: 2 AN: 64266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3436

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 895574

Other (OTH) AF: 0.00 AC: 0 AN: 49346

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.79
PhyloP100		-0.42
PromoterAI		-0.022	Neutral

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: rs1166335966; hg19: chr11-2182336;