2-216694687-C-G

Variant names:

• chr2-216694687-C-G
• NM_000599.4:c.89G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000599.4(IGFBP5):​c.89G>C​(p.Cys30Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGFBP5 NM_000599.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72
• 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]

TESHL (HGNC:52740): (testicular germ cell expressed HSF2 interacting lncRNA)

IGFBP-AS1 (HGNC:55655): (IGFBP5 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4	c.89G>C	p.Cys30Ser	missense_variant	Exon 1 of 4	ENST00000233813.5	NP_000590.1
IGFBP-AS1	NR_187138.1	n.242C>G		non_coding_transcript_exon_variant	Exon 1 of 6
IGFBP-AS1	NR_187139.1	n.242C>G		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP5	ENST00000233813.5	c.89G>C	p.Cys30Ser	missense_variant	Exon 1 of 4	1	NM_000599.4	ENSP00000233813.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89G>C (p.C30S) alteration is located in exon 1 (coding exon 1) of the IGFBP5 gene. This alteration results from a G to C substitution at nucleotide position 89, causing the cysteine (C) at amino acid position 30 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	H;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.64
MutPred		0.91		Loss of catalytic residue at P29 (P = 0.0047);Loss of catalytic residue at P29 (P = 0.0047);
MVP		0.88
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.0026	Neutral
Varity_R		0.93
gMVP		0.98
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr2-217559410;