chr11-2160901-G-A

Variant names:

• chr11-2160901-G-A
• rs80356663
• NM_000207.3:c.71C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 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
• Publications: 21 publications found

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr11-2160901-G-T is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 13388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.9004 (below the threshold of 3.09). Trascript score misZ: 0.85584 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperproinsulinemia, diabetes mellitus, permanent neonatal 4, type 1 diabetes mellitus 2, maturity-onset diabetes of the young type 10, monogenic diabetes, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young.
• 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 VariationId is 36401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.71C>T	p.Ala24Val	missense	Exon 2 of 3	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.71C>T	p.Ala24Val	missense	Exon 2 of 5	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.71C>T	p.Ala24Val	missense	Exon 2 of 3	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.71C>T	p.Ala24Val	missense	Exon 2 of 3	ENSP00000370731.5	P01308-1
	INS-IGF2	ENST00000397270.1	TSL:1	c.71C>T	p.Ala24Val	missense	Exon 2 of 5	ENSP00000380440.1	F8WCM5-1
	INS	ENST00000250971.7	TSL:1	c.71C>T	p.Ala24Val	missense	Exon 2 of 3	ENSP00000250971.3	P01308-1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Neonatal diabetes mellitus (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.55	N
PhyloP100		3.9
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.035	D
Polyphen		0.96	D
Vest4		0.47
MutPred		0.40		Gain of sheet (P = 0.0016)
MVP		0.61
MPC		0.26
ClinPred		0.60	D
GERP RS		2.6
PromoterAI		0.0011	Neutral
Varity_R		0.14
gMVP		0.87
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80356663; hg19: chr11-2182131;