rs571342427

Variant names:

• chr11-2161289-T-C
• rs571342427
• ENST00000729705.1:n.174+2375T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-2161289-T-C
• chr11-2161289-T-G

Variant summary

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

The ENST00000729705.1(ENSG00000295384):​n.174+2375T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 328,176 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00075 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -4.11
• Publications: 6 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-2161289-T-C is Benign according to our data. Variant chr11-2161289-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435509.

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.-139A>G		upstream_gene	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-139A>G		upstream_gene	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.-165A>G		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+2375T>C		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.225+2375T>C		intron	N/A
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-139A>G		upstream_gene	N/A	ENSP00000370731.5	P01308-1

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 151988 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000869 AC: 153 AN: 176070 Hom.: 1 Cov.: 0 AF XY: 0.000951 AC XY: 85 AN XY: 89392

African (AFR) AF: 0.000155 AC: 1 AN: 6446

American (AMR) AF: 0.000680 AC: 5 AN: 7350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6260

East Asian (EAS) AF: 0.00 AC: 0 AN: 13968

South Asian (SAS) AF: 0.000519 AC: 6 AN: 11562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 862

European-Non Finnish (NFE) AF: 0.00122 AC: 132 AN: 108534

Other (OTH) AF: 0.000824 AC: 9 AN: 10920

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152106 Hom.: 1 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74376

African (AFR) AF: 0.000313 AC: 13 AN: 41510

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00124 AC: 84 AN: 67936

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000854

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	INS-related disorder (1)
-	1	-	not specified (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.2
DANN	Benign	0.88
PhyloP100		-4.1
PromoterAI		0.00010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs571342427; hg19: chr11-2182519;