rs42531

Variant names:

• chr7-94423351-G-A
• rs42531
• NM_000089.4:c.2565+233G>A

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+233G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 545,616 control chromosomes in the GnomAD database, including 22,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5258 hom., cov: 31)
  • Exomes 𝑓: 0.30 (17712 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00500
• Publications: 8 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=-0.83).
• BP6: Variant 7-94423351-G-A is Benign according to our data. Variant chr7-94423351-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.2565+233G>A		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+233G>A		intron_variant	Intron 40 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000481570.5	n.881G>A		non_coding_transcript_exon_variant	Exon 1 of 8	2
COL1A2	ENST00000497316.5	n.*233G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36000 AN: 151834 Hom.: 5260 Cov.: 31

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.296 AC: 116582 AN: 393662 Hom.: 17712 Cov.: 4 AF XY: 0.296 AC XY: 62360 AN XY: 210742

African (AFR) AF: 0.0564 AC: 627 AN: 11114

American (AMR) AF: 0.250 AC: 4387 AN: 17538

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 3420 AN: 11618

East Asian (EAS) AF: 0.263 AC: 6470 AN: 24614

South Asian (SAS) AF: 0.283 AC: 12634 AN: 44652

European-Finnish (FIN) AF: 0.363 AC: 7931 AN: 21824

Middle Eastern (MID) AF: 0.244 AC: 408 AN: 1670

European-Non Finnish (NFE) AF: 0.313 AC: 74496 AN: 238168

Other (OTH) AF: 0.276 AC: 6209 AN: 22464

GnomAD4 genome AF: 0.237 AC: 35986 AN: 151954 Hom.: 5258 Cov.: 31 AF XY: 0.241 AC XY: 17927 AN XY: 74278

African (AFR) AF: 0.0611 AC: 2535 AN: 41488

American (AMR) AF: 0.256 AC: 3900 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3470

East Asian (EAS) AF: 0.255 AC: 1313 AN: 5146

South Asian (SAS) AF: 0.277 AC: 1335 AN: 4820

European-Finnish (FIN) AF: 0.378 AC: 3984 AN: 10546

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

European-Non Finnish (NFE) AF: 0.311 AC: 21121 AN: 67918

Other (OTH) AF: 0.230 AC: 485 AN: 2110

Alfa AF: 0.265 Hom.: 741

Bravo AF: 0.220

Asia WGS AF: 0.232 AC: 805 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.39
PhyloP100		0.0050
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: rs42531; hg19: chr7-94052663;