rs406226

Variant names:

• chr7-94404488-A-G
• rs406226
• NM_000089.4:c.280-68A>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.280-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,557,980 control chromosomes in the GnomAD database, including 29,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2533 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26752 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.60
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-94404488-A-G is Benign according to our data. Variant chr7-94404488-A-G is described in ClinVar as Benign. ClinVar VariationId is 674810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.29 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.280-68A>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.280-68A>G		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.280-68A>G		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.280-68A>G		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26832 AN: 152126 Hom.: 2525 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.190 AC: 266858 AN: 1405736 Hom.: 26752 AF XY: 0.186 AC XY: 130764 AN XY: 702610

African (AFR) AF: 0.146 AC: 4700 AN: 32254

American (AMR) AF: 0.350 AC: 15580 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4548 AN: 25748

East Asian (EAS) AF: 0.109 AC: 4294 AN: 39424

South Asian (SAS) AF: 0.106 AC: 9040 AN: 85026

European-Finnish (FIN) AF: 0.0989 AC: 5276 AN: 53354

Middle Eastern (MID) AF: 0.152 AC: 615 AN: 4044

European-Non Finnish (NFE) AF: 0.199 AC: 212053 AN: 1063040

Other (OTH) AF: 0.184 AC: 10752 AN: 58318

GnomAD4 genome AF: 0.176 AC: 26863 AN: 152244 Hom.: 2533 Cov.: 32 AF XY: 0.173 AC XY: 12910 AN XY: 74454

African (AFR) AF: 0.148 AC: 6129 AN: 41546

American (AMR) AF: 0.298 AC: 4550 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3468

East Asian (EAS) AF: 0.115 AC: 595 AN: 5170

South Asian (SAS) AF: 0.106 AC: 510 AN: 4828

European-Finnish (FIN) AF: 0.0785 AC: 834 AN: 10622

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13173 AN: 68002

Other (OTH) AF: 0.188 AC: 398 AN: 2116

Alfa AF: 0.191 Hom.: 10998

Bravo AF: 0.193

Asia WGS AF: 0.109 AC: 380 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.47
PhyloP100		-2.6
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: rs406226; hg19: chr7-94033800;