rs1051986248

Variant names:

• chr11-2161146-C-T
• rs1051986248
• ENST00000250971.7:c.-22G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001185097.2(INS):​c.-22G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 852,456 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: INS NM_001185097.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.07
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-2161146-C-T is Benign according to our data. Variant chr11-2161146-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435505.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001185097.2. 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+22G>A		intron	N/A	NP_000198.1	P01308-1
	INS	NM_001185097.2		c.-22G>A		5_prime_UTR	Exon 1 of 3	NP_001172026.1	I3WAC9
	INS	NM_001185098.2		c.-175G>A		5_prime_UTR	Exon 1 of 2	NP_001172027.1	P01308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000250971.7	TSL:1	c.-22G>A		5_prime_UTR	Exon 1 of 3	ENSP00000250971.3	P01308-1
	INS	ENST00000397262.5	TSL:1	c.-175G>A		5_prime_UTR	Exon 1 of 2	ENSP00000380432.1	P01308-1
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-18+22G>A		intron	N/A	ENSP00000370731.5	P01308-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151162 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 13 AN: 701294 Hom.: 0 Cov.: 9 AF XY: 0.0000225 AC XY: 8 AN XY: 356216

African (AFR) AF: 0.000119 AC: 2 AN: 16766

American (AMR) AF: 0.00 AC: 0 AN: 20798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15468

East Asian (EAS) AF: 0.0000311 AC: 1 AN: 32198

South Asian (SAS) AF: 0.0000773 AC: 4 AN: 51756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2518

European-Non Finnish (NFE) AF: 0.0000121 AC: 6 AN: 497774

Other (OTH) AF: 0.00 AC: 0 AN: 34402

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151162 Hom.: 0 Cov.: 35 AF XY: 0.0000135 AC XY: 1 AN XY: 73818

African (AFR) AF: 0.0000495 AC: 2 AN: 40444

American (AMR) AF: 0.00 AC: 0 AN: 15270

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: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.61
PhyloP100		-1.1
PromoterAI		-0.045	Neutral
Mutation Taster		=292/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1051986248;

hg19: chr11-2182376;