11-2160994-A-T

Position:

chr11-2160994-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000381330.5(INS):c.-17-6T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,609,954 control chromosomes in the GnomAD database, including 415,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 32035 hom., cov: 35)

Exomes 𝑓: 0.72 ( 383950 hom. )

Consequence

INS
ENST00000381330.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.1228

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0740

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:):

INS-IGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-2160994-A-T is Benign according to our data. Variant chr11-2160994-A-T is described in ClinVar as [Benign]. Clinvar id is 304059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3 linkuse as main transcript	c.-17-6T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4 linkuse as main transcript	n.43-6T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.-17-6T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000207.3	ENSP00000370731	P1	P01308-1

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92830

AN:

152032

Hom.:

32028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.709

Gnomad EAS

AF:

0.947

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.792

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.719

Gnomad OTH

AF:

0.669

GnomAD3 exomes

AF:

0.734

AC:

178240

AN:

242726

Hom.:

67953

AF XY:

0.745

AC XY:

98674

AN XY:

132380

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.703

Gnomad EAS exome

AF:

0.953

Gnomad SAS exome

AF:

0.833

Gnomad FIN exome

AF:

0.797

Gnomad NFE exome

AF:

0.720

Gnomad OTH exome

AF:

0.737

GnomAD4 exome

AF:

0.720

AC:

1049977

AN:

1457804

Hom.:

383950

Cov.:

AF XY:

0.725

AC XY:

525501

AN XY:

725156

show subpopulations

Gnomad4 AFR exome

AF:

0.245

Gnomad4 AMR exome

AF:

0.762

Gnomad4 ASJ exome

AF:

0.705

Gnomad4 EAS exome

AF:

0.959

Gnomad4 SAS exome

AF:

0.827

Gnomad4 FIN exome

AF:

0.792

Gnomad4 NFE exome

AF:

0.713

Gnomad4 OTH exome

AF:

0.716

GnomAD4 genome

AF:

0.610

AC:

92854

AN:

152150

Hom.:

32035

Cov.:

AF XY:

0.624

AC XY:

46388

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.725

Gnomad4 ASJ

AF:

0.709

Gnomad4 EAS

AF:

0.948

Gnomad4 SAS

AF:

0.831

Gnomad4 FIN

AF:

0.792

Gnomad4 NFE

AF:

0.719

Gnomad4 OTH

AF:

0.673

Alfa

AF:

0.676

Hom.:

6698

Bravo

AF:

0.588

Asia WGS

AF:

0.841

AC:

2925

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16380501, 17327440, 22357962, 20628762) -

Transient Neonatal Diabetes, Dominant/Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive DOPA responsive dystonia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity-onset diabetes of the young type 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.2

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.12

dbscSNV1_RF

Benign

0.39

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.38

Position offset: -6

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