rs1554921033

Variant names:

• chr11-2161189-T-G
• rs1554921033
• NM_000207.3:c.-39A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001042376.3(INS-IGF2):​c.-39A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000492 in 488,074 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: INS-IGF2 NM_001042376.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.494
• 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-2161189-T-G is Benign according to our data. Variant chr11-2161189-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 431444.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.-39A>C		5_prime_UTR	Exon 1 of 3	NP_000198.1
	INS-IGF2	NM_001042376.3		c.-39A>C		5_prime_UTR	Exon 1 of 5	NP_001035835.1
	INS	NM_001185097.2		c.-65A>C		5_prime_UTR	Exon 1 of 3	NP_001172026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-39A>C		5_prime_UTR	Exon 1 of 3	ENSP00000370731.5
	INS-IGF2	ENST00000397270.1	TSL:1	c.-39A>C		5_prime_UTR	Exon 1 of 5	ENSP00000380440.1
	INS	ENST00000250971.7	TSL:1	c.-65A>C		5_prime_UTR	Exon 1 of 3	ENSP00000250971.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.0000492 AC: 24 AN: 488074 Hom.: 0 Cov.: 6 AF XY: 0.0000710 AC XY: 18 AN XY: 253534

African (AFR) AF: 0.00 AC: 0 AN: 12860

American (AMR) AF: 0.00 AC: 0 AN: 18358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13726

East Asian (EAS) AF: 0.00 AC: 0 AN: 30718

South Asian (SAS) AF: 0.000530 AC: 24 AN: 45294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2022

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 309600

Other (OTH) AF: 0.00 AC: 0 AN: 27050

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)
-	-	-	Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.48
PhyloP100		-0.49
PromoterAI		0.016	Neutral
Mutation Taster		=28/272	disease causing (ClinVar)

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: rs1554921033; hg19: chr11-2182419;