rs42530

Variant names:

• chr7-94423183-A-G
• rs42530
• NM_000089.4:c.2565+65A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000089.4(COL1A2):​c.2565+65A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,577,000 control chromosomes in the GnomAD database, including 70,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5290 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65184 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.399
• Publications: 13 publications found

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]

COL1A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, arthrochalasia type, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Ehlers-Danlos syndrome, cardiac valvular type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, PanelApp Australia, Orphanet, G2P
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-94423183-A-G is Benign according to our data. Variant chr7-94423183-A-G is described in ClinVar as Benign. ClinVar VariationId is 674831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.2565+65A>G		intron_variant	Intron 40 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.2565+65A>G		intron_variant	Intron 40 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000481570.5	n.713A>G		non_coding_transcript_exon_variant	Exon 1 of 8	2
COL1A2	ENST00000497316.5	n.*65A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36110 AN: 152008 Hom.: 5292 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.299 AC: 425711 AN: 1424874 Hom.: 65184 Cov.: 23 AF XY: 0.300 AC XY: 213180 AN XY: 710876

African (AFR) AF: 0.0478 AC: 1567 AN: 32754

American (AMR) AF: 0.243 AC: 10817 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7517 AN: 25854

East Asian (EAS) AF: 0.259 AC: 10217 AN: 39504

South Asian (SAS) AF: 0.286 AC: 24377 AN: 85274

European-Finnish (FIN) AF: 0.366 AC: 19404 AN: 52962

Middle Eastern (MID) AF: 0.244 AC: 1199 AN: 4918

European-Non Finnish (NFE) AF: 0.309 AC: 334025 AN: 1079958

Other (OTH) AF: 0.281 AC: 16588 AN: 59128

GnomAD4 genome AF: 0.237 AC: 36097 AN: 152126 Hom.: 5290 Cov.: 32 AF XY: 0.242 AC XY: 17997 AN XY: 74352

African (AFR) AF: 0.0612 AC: 2541 AN: 41538

American (AMR) AF: 0.258 AC: 3939 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 981 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5166

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4820

European-Finnish (FIN) AF: 0.379 AC: 3995 AN: 10554

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21146 AN: 67978

Other (OTH) AF: 0.231 AC: 488 AN: 2112

Alfa AF: 0.288 Hom.: 14227

Bravo AF: 0.221

Asia WGS AF: 0.232 AC: 806 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.71
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs42530; hg19: chr7-94052495; COSMIC: COSV51957117; COSMIC: COSV51957117;