11-2160905-C-T

Position:

chr11-2160905-C-T

Variant summary

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

The NM_000207.3(INS):c.67G>A(p.Ala23Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,612,632 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 35)

Exomes 𝑓: 0.00061 ( 11 hom. )

Consequence

INS
NM_000207.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.0340

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015170068).

BP6

Variant 11-2160905-C-T is Benign according to our data. Variant chr11-2160905-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 730224.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr11-2160905-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000315 (48/152318) while in subpopulation EAS AF= 0.00811 (42/5176). AF 95% confidence interval is 0.00617. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3 linkuse as main transcript	c.67G>A	p.Ala23Thr	missense_variant	2/3	ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4 linkuse as main transcript	n.126G>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.67G>A	p.Ala23Thr	missense_variant	2/3	1	NM_000207.3	ENSP00000370731	P1	P01308-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00810

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000388

AC:

AN:

247280

Hom.:

AF XY:

0.000372

AC XY:

AN XY:

134466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00468

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000608

AC:

888

AN:

1460314

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

450

AN XY:

726480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0213

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000315

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00811

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000455

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Diabetes mellitus type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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.However, more evidence is required to confer the association of this particular variant A23S/rs13306444 with Type l diabetes mellitus -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 20, 2023

- -

INS-IGF2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Transient Neonatal Diabetes, Dominant/Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

- -

Maturity-onset diabetes of the young type 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

2.8

DANN

Benign

0.94

DEOGEN2

Benign

0.015

T;T;T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.19

T;.;.;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.015

T;T;T;T;T;T

MetaSVM

Uncertain

0.037

MutationAssessor

Benign

0.0

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

0.20

N;N;N;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.17

T;T;T;T;T;T

Sift4G

Benign

0.45

T;T;T;T;.;T

Polyphen

0.083

B;B;B;B;.;B

Vest4

0.18

MVP

0.061

MPC

0.25

ClinPred

0.027

GERP RS

-0.26

Varity_R

0.084

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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