rs752453618

chr7-94424433-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_000089.4(COL1A2):c.2663C>G(p.Ala888Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: COL1A2 NM_000089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000089.4
• PP2: Missense variant where missense usually causes diseases, COL1A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.4121698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.2663C>G	p.Ala888Gly	missense_variant	41/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.2663C>G	p.Ala888Gly	missense_variant	41/52	1	NM_000089.4	P1
COL1A2	ENST00000469732.1	n.446C>G		non_coding_transcript_exon_variant	1/4	2
COL1A2	ENST00000481570.5	n.1963C>G		non_coding_transcript_exon_variant	1/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251448 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135892

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461724 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727170

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine with glycine at codon 888 of the COL1A2 protein (p.Ala888Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs752453618, ExAC 0.001%). This variant has been reported in an individual in the Osteogenesis Imperfecta Leiden Open-source Variation Database (PMID: 21520333). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.85	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.034	D;D
Polyphen		0.016	B;.
Vest4		0.30
MutPred		0.48		Loss of relative solvent accessibility (P = 0.0306);.;
MVP		0.86
MPC		0.21
ClinPred		0.49	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs752453618; hg19: chr7-94053745;