11-2160901-G-T

Position:

• chr11-2160901-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000207.3(INS):​c.71C>A​(p.Ala24Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:4 O: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: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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 11-2160901-G-T is Pathogenic according to our data. Variant chr11-2160901-G-T is described in ClinVar as [Likely_risk_allele]. Clinvar id is 13388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_risk_allele=1, not_provided=2}. Variant chr11-2160901-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.71C>A	p.Ala24Asp	missense_variant	2/3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.71C>A	p.Ala24Asp	missense_variant	2/3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.71C>A	p.Ala24Asp	missense_variant	2/5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes mellitus, permanent neonatal 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
Likely risk allele, 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.Sufficient evidence is found to confer the association of this particular variant A24D/rs80356663 with permanent neonatal diabetes. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 24 of the INS protein (p.Ala24Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13388). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 19, 2020	DNA sequence analysis of the INS gene demonstrated a sequence change, c.71C>A, in exon 2 that results in an amino acid change, p.Ala24Asp. This sequence change is absent from large population databases such as ExAC and gnomAD (dbSNP rs80356663). The p.Ala24Asp change affects a highly conserved amino acid residue located in region of insulin protein (signal peptide cleavage site) that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala24Asp substitution. This particular amino acid change has been described in multiple patients with permanent neonatal diabetes (PMIDs: 17855560, 18162506, and 18171712). Functional studies have shown that p.Ala24Asp mutant results in aberrant processing of proinsulin to insulin and retention of proinsulin in the endoplasmic reticulum (PMIDs: 19952343, 22357960). Pathogenic variants in INS cause permanent neonatal diabetes [OMIM# 606176]. Most cases of INS-associated neonatal diabetes are inherited in an autosomal dominant manner; however autosomal recessive cases have also been reported. -

Permanent neonatal diabetes mellitus Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T;D;D;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;.;.;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.55	N;.;.;.;.;.
PROVEAN	Uncertain	-2.5	D;N;N;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;.;D
Polyphen		1.0	D;P;P;P;.;P
Vest4		0.81
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.72
MPC		0.39
ClinPred		0.74	D
GERP RS		2.6
Varity_R		0.84
gMVP		0.95

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;