Variant 11-2159896-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate

The NM_000207.3(INS):c.289A>C(p.Thr97Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T97S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

INS
NM_000207.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.778

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000207.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2159895-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 617648.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_risk_allele=1}.

PP5

Variant 11-2159896-T-G is Pathogenic according to our data. Variant chr11-2159896-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1336487.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3 linkuse as main transcript	c.289A>C	p.Thr97Pro	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4 linkuse as main transcript	n.246+889A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.289A>C	p.Thr97Pro	missense_variant	3/3	1	NM_000207.3	P1	P01308-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;D;D;.

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.64

.;.;T;T

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.58

D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.0

M;M;M;.

MutationTaster

Benign

1.0

D;D;N;N;N;N

PROVEAN

Benign

-0.78

N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.066

T;T;T;T

Polyphen

0.99

D;D;D;P

Vest4

0.25

MutPred

0.63

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;

MVP

0.97

MPC

1.3

ClinPred

0.46

GERP RS

-2.0

La Branchor

0.88

Varity_R

0.90

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over