chr7-94403441-A-G

Variant names:

• chr7-94403441-A-G
• rs1858822
• NM_000089.4:c.280-1115A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000089.4(COL1A2):​c.280-1115A>G variant causes a intron change. The variant allele was found at a frequency of 0.32 in 152,044 control chromosomes in the GnomAD database, including 8,751 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8751 hom., cov: 33)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 5 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):

• COL1A2-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• COL1A2-related osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type, 2

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

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

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

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

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

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.280-1115A>G		intron	N/A	NP_000080.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.280-1115A>G		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.280-1115A>G		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.280-1115A>G		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48605 AN: 151926 Hom.: 8751 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 48604 AN: 152044 Hom.: 8751 Cov.: 33 AF XY: 0.326 AC XY: 24258 AN XY: 74316

African (AFR) AF: 0.174 AC: 7215 AN: 41508

American (AMR) AF: 0.270 AC: 4131 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3468

East Asian (EAS) AF: 0.393 AC: 2028 AN: 5166

South Asian (SAS) AF: 0.445 AC: 2140 AN: 4812

European-Finnish (FIN) AF: 0.540 AC: 5706 AN: 10568

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25228 AN: 67930

Other (OTH) AF: 0.289 AC: 611 AN: 2114

Alfa AF: 0.352 Hom.: 37548

Bravo AF: 0.292

Asia WGS AF: 0.386 AC: 1337 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.64
PhyloP100		4.0
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: rs1858822; hg19: chr7-94032753;