rs148981948

Variant names:

• chr2-216678165-G-A
• rs148981948
• NM_000599.4:c.634C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-216678165-G-A
• chr2-216678165-G-C
• chr2-216678165-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000599.4(IGFBP5):​c.634C>T​(p.Arg212Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000808 in 1,595,442 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: IGFBP5 NM_000599.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4	c.634C>T	p.Arg212Cys	missense_variant	Exon 3 of 4	ENST00000233813.5	NP_000590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP5	ENST00000233813.5	c.634C>T	p.Arg212Cys	missense_variant	Exon 3 of 4	1	NM_000599.4	ENSP00000233813.4

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000322 AC: 78 AN: 242324 AF XY: 0.000305

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000579

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000834 AC: 1204 AN: 1443128 Hom.: 1 Cov.: 30 AF XY: 0.000853 AC XY: 612 AN XY: 717320

African (AFR) AF: 0.000152 AC: 5 AN: 32972

American (AMR) AF: 0.000185 AC: 8 AN: 43280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38762

South Asian (SAS) AF: 0.000240 AC: 20 AN: 83500

European-Finnish (FIN) AF: 0.000339 AC: 18 AN: 53088

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.00100 AC: 1106 AN: 1100532

Other (OTH) AF: 0.000722 AC: 43 AN: 59566

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74472

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000655 Hom.: 1

Bravo AF: 0.000552

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.634C>T (p.R212C) alteration is located in exon 3 (coding exon 3) of the IGFBP5 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the arginine (R) at amino acid position 212 to be replaced by a cysteine (C). 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	0.93
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.68
MPC		1.9
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.81
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs148981948; hg19: chr2-217542888;