chr2-216676765-T-G

Variant names:

• chr2-216676765-T-G
• NM_000599.4:c.805A>C

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.805A>C​(p.Ser269Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: IGFBP5 NM_000599.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62
• 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=0.212948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4	c.805A>C	p.Ser269Arg	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.805A>C	p.Ser269Arg	missense_variant	Exon 4 of 4	1	NM_000599.4	ENSP00000233813.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.805A>C (p.S269R) alteration is located in exon 4 (coding exon 4) of the IGFBP5 gene. This alteration results from a A to C substitution at nucleotide position 805, causing the serine (S) at amino acid position 269 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.070
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.74	P
Vest4		0.35
MutPred		0.20		Loss of glycosylation at S269 (P = 0.0196);
MVP		0.36
MPC		1.5
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.78
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr2-217541488;