2-216676808-C-T

Variant names:

• chr2-216676808-C-T
• rs1688906146
• NM_000599.4:c.762G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000599.4(IGFBP5):​c.762G>A​(p.Met254Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IGFBP5 NM_000599.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.972
• Publications: 0 publications found

Genes affected

IGFBP5 (HGNC:5474): (insulin like growth factor binding protein 5) Enables insulin-like growth factor I binding activity. Involved in several processes, including cellular response to cAMP; regulation of smooth muscle cell migration; and regulation of smooth muscle cell proliferation. Part of insulin-like growth factor ternary complex. Biomarker of pulmonary fibrosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08722898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4	c.762G>A	p.Met254Ile	missense_variant	Exon 4 of 4	ENST00000233813.5	NP_000590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP5	ENST00000233813.5	c.762G>A	p.Met254Ile	missense_variant	Exon 4 of 4	1	NM_000599.4	ENSP00000233813.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.97
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.081
Sift	Benign	0.65	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.50		Gain of catalytic residue at M254 (P = 0.0868);
MVP		0.30
MPC		0.71
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.74
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1688906146; hg19: chr2-217541531; COSMIC: COSV52083566; COSMIC: COSV52083566;