11-2160956-G-C

Variant names:

• chr11-2160956-G-C
• rs121908278
• NM_000207.3:c.16C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000207.3(INS):​c.16C>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,054 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. R6H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2160955-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36569792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.16C>G	p.Arg6Gly	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.16C>G	p.Arg6Gly	missense_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.16C>G	p.Arg6Gly	missense_variant	Exon 2 of 5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246320 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460054 Hom.: 0 Cov.: 88 AF XY: 0.00000138 AC XY: 1 AN XY: 726366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.098	T;D;D;D;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.86	D;.;.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.55	N;.;.;.;.;.
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;.;T
Polyphen		0.59	P;B;B;B;.;B
Vest4		0.50
MutPred		0.43		Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);
MVP		0.58
MPC		0.33
ClinPred		0.28	T
GERP RS		1.7
Varity_R		0.27
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs121908278; hg19: chr11-2182186; COSMIC: COSV99171170; COSMIC: COSV99171170;