11-2160905-C-A

Variant names:

• chr11-2160905-C-A
• rs13306444
• NM_000207.3:c.67G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_000207.3(INS):​c.67G>T​(p.Ala23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000207.3
• 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 type 1 diabetes mellitus 2, diabetes mellitus, permanent neonatal 4, monogenic diabetes, transient neonatal diabetes mellitus, maturity-onset diabetes of the young type 10, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, hyperproinsulinemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.113307714).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247280 AF XY: 0.00000744

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460314 Hom.: 0 Cov.: 88 AF XY: 0.0000248 AC XY: 18 AN XY: 726480

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.0000671 AC: 3 AN: 44708

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26118

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52122

Gnomad4 NFE exome AF: 0.0000234 AC: 26 AN: 1111824

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482556 AN: 0.0000482556

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294023 AN: 0.0000294023

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	0.30
DANN	Benign	0.85
DEOGEN2	Benign	0.0060	T;T;T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.045	T;.;.;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Uncertain	0.067	D
MutationAssessor	Benign	0.0	N;.;.;.;.;.
PROVEAN	Benign	0.61	N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.17	T;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;.;T
Polyphen		0.0090	B;B;B;B;.;B
Vest4		0.14
MutPred		0.41		Gain of glycosylation at A23 (P = 0.0148);Gain of glycosylation at A23 (P = 0.0148);Gain of glycosylation at A23 (P = 0.0148);Gain of glycosylation at A23 (P = 0.0148);Gain of glycosylation at A23 (P = 0.0148);Gain of glycosylation at A23 (P = 0.0148);
MVP		0.13
MPC		0.24
ClinPred		0.047	T
GERP RS		-0.26
Varity_R		0.054
gMVP		0.73
Mutation Taster		=3/97	disease causing

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: rs13306444; hg19: chr11-2182135; COSMIC: COSV51747007; COSMIC: COSV51747007;