rs80356663

Positions:

• chr11-2160901-G-A
• chr11-2160901-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_000207.3(INS):​c.71C>T​(p.Ala24Val) variant causes a missense change. 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. A24D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.93

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-IGF2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2160901-G-T is described in Lovd as [Pathogenic].
• PP5: Variant 11-2160901-G-A is Pathogenic according to our data. Variant chr11-2160901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2160901-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.71C>T	p.Ala24Val	missense_variant	2/3	ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4	n.130C>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.71C>T	p.Ala24Val	missense_variant	2/3	1	NM_000207.3	ENSP00000370731	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 35

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 09, 2019

DNA sequence analysis of the INS gene demonstrated a sequence change, c.71C>T, in exon 2 that results in an amino acid change, p.Ala24Val. The p.Ala24Val change affects a highly conserved amino acid residue located in a domain of the INS protein that is not known to be functional. The p.Ala24Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This variant has not been described in large population databases such as EXAC and gnomAD. The p.Ala24Val variant has been reported in the heterozygous state in a family with permanent neonatal diabetes (PMID: 25765664). Furthermore, a different pathogenic sequence change affecting the same amino acid residue (p.Ala24Asp) has been described in multiple patients with permanent neonatal diabetes (PMIDs: 17855560, 22357960, 20034470). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T;T;T;.;.
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;.;.;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.55	N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.020	D;T;T;T;T;T
Sift4G	Uncertain	0.035	D;T;T;T;.;T
Polyphen		0.96	D;P;P;P;.;B
Vest4		0.47
MutPred		0.40		Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);
MVP		0.61
MPC		0.26
ClinPred		0.60	D
GERP RS		2.6
Varity_R		0.40
gMVP		0.87

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

Other links and lift over

dbSNP: rs80356663; hg19: chr11-2182131;