rs3842738

Variant names:

• chr11-2161265-C-G
• rs3842738
• ENST00000729705.1:n.174+2351C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-2161265-C-G
• chr11-2161265-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000729705.1(ENSG00000295384):​n.174+2351C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.942 in 396,288 control chromosomes in the GnomAD database, including 179,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61547 hom., cov: 35)
  • Exomes 𝑓: 0.98 (118034 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-2161265-C-G is Benign according to our data. Variant chr11-2161265-C-G is described in ClinVar as Benign. ClinVar VariationId is 1291923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.-115G>C		upstream_gene_variant		ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.-115G>C		upstream_gene_variant		1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.-115G>C		upstream_gene_variant		1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134097 AN: 152054 Hom.: 61515 Cov.: 35

Gnomad AFR AF: 0.594

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.950

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.913

GnomAD4 exome AF: 0.980 AC: 239303 AN: 244116 Hom.: 118034 Cov.: 3 AF XY: 0.983 AC XY: 122299 AN XY: 124464

African (AFR) AF: 0.587 AC: 4965 AN: 8460

American (AMR) AF: 0.968 AC: 9878 AN: 10204

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 8550 AN: 8676

East Asian (EAS) AF: 1.00 AC: 19804 AN: 19806

South Asian (SAS) AF: 0.999 AC: 14398 AN: 14414

European-Finnish (FIN) AF: 1.00 AC: 15022 AN: 15022

Middle Eastern (MID) AF: 0.978 AC: 1148 AN: 1174

European-Non Finnish (NFE) AF: 0.998 AC: 150866 AN: 151114

Other (OTH) AF: 0.962 AC: 14672 AN: 15246

GnomAD4 genome AF: 0.882 AC: 134181 AN: 152172 Hom.: 61547 Cov.: 35 AF XY: 0.887 AC XY: 66019 AN XY: 74406

African (AFR) AF: 0.594 AC: 24641 AN: 41472

American (AMR) AF: 0.951 AC: 14544 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3411 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5159 AN: 5160

South Asian (SAS) AF: 0.998 AC: 4821 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67850 AN: 67988

Other (OTH) AF: 0.914 AC: 1933 AN: 2114

Alfa AF: 0.931 Hom.: 7943

Bravo AF: 0.864

Asia WGS AF: 0.977 AC: 3399 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.60
DANN	Benign	0.38
PhyloP100		-1.6
PromoterAI		-0.024	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3842738; hg19: chr11-2182495;