11-2161147-G-T

Variant names:

• chr11-2161147-G-T
• rs568856178
• ENST00000250971.7:c.-23C>A

Variant summary

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

The ENST00000250971.7(INS):​c.-23C>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 0.00000234 in 853,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INS ENST00000250971.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.11
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000250971.7. 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.-18+21C>A		intron	N/A	NP_000198.1
	INS	NM_001185097.2		c.-23C>A		5_prime_UTR	Exon 1 of 3	NP_001172026.1
	INS	NM_001185098.2		c.-176C>A		5_prime_UTR	Exon 1 of 2	NP_001172027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000250971.7	TSL:1	c.-23C>A		5_prime_UTR	Exon 1 of 3	ENSP00000250971.3
	INS	ENST00000397262.5	TSL:1	c.-176C>A		5_prime_UTR	Exon 1 of 2	ENSP00000380432.1
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-18+21C>A		intron	N/A	ENSP00000370731.5

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151108 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 1 AN: 701936 Hom.: 0 Cov.: 9 AF XY: 0.00000280 AC XY: 1 AN XY: 356562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16770

American (AMR) AF: 0.00 AC: 0 AN: 20802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15462

East Asian (EAS) AF: 0.00 AC: 0 AN: 32208

South Asian (SAS) AF: 0.00 AC: 0 AN: 51768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2516

European-Non Finnish (NFE) AF: 0.00000201 AC: 1 AN: 498342

Other (OTH) AF: 0.00 AC: 0 AN: 34446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151108 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 73804

African (AFR) AF: 0.00 AC: 0 AN: 40412

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.048
DANN	Benign	0.50
PhyloP100		-2.1
PromoterAI		-0.036	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs568856178; hg19: chr11-2182377;