rs571342427

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000207.3(INS):c.-139A>G variant causes a upstream gene 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

INS
NM_000207.3 upstream_gene

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -4.11

Variant links:

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 links:

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]

INS-IGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 id is 435509.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152106) while in subpopulation NFE AF= 0.00124 (84/67936). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3 link	c.-139A>G		upstream_gene_variant		ENST00000381330.5	NP_000198.1	P01308-1I3WAC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 link	c.-139A>G		upstream_gene_variant		1	NM_000207.3	ENSP00000370731.5		P01308-1
INS-IGF2	ENST00000397270.1 link	c.-139A>G		upstream_gene_variant		1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

151988

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000951

AC XY:

AN XY:

89392

show subpopulations

Gnomad4 AFR exome

AF:

0.000155

Gnomad4 AMR exome

AF:

0.000680

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000519

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.000824

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152106

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00124

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000555

Hom.:

Bravo

AF:

0.000854

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

INS: BP5, BS1 -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Feb 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

INS-related disorder

Uncertain:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The INS c.-139A>G variant is located in the 5' untranslated region. This variant was reported in an individual with type 2 diabetes mellitus (reported as c.−80A>G in Malecki et al 2006. PubMed ID: 16741735). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. This variant has interpretations of likely benign (3) to uncertain significance (1) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/435509/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Type 2 diabetes mellitus

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.Though rs571342427 is prevalent in Type Il Diabetes Mellitus cases, more evidence is required to ascertain the significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.2

DANN

Benign

0.88

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over