rs2521206

Variant names:

• chr7-94409875-A-G
• rs2521206
• NM_000089.4:c.1035+54A>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.1035+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,510,184 control chromosomes in the GnomAD database, including 41,184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5152 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36032 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.795
• Publications: 21 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

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, ClinGen
• osteogenesis imperfecta type 2

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

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, 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=-0.82).
• BP6: Variant 7-94409875-A-G is Benign according to our data. Variant chr7-94409875-A-G is described in ClinVar as Benign. ClinVar VariationId is 675065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 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.1035+54A>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.1035+54A>G		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.1035+54A>G		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.1035+54A>G		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37686 AN: 151844 Hom.: 5129 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.223 AC: 303124 AN: 1358222 Hom.: 36032 AF XY: 0.223 AC XY: 152161 AN XY: 681342

African (AFR) AF: 0.312 AC: 9848 AN: 31558

American (AMR) AF: 0.215 AC: 9492 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3486 AN: 25396

East Asian (EAS) AF: 0.494 AC: 19407 AN: 39246

South Asian (SAS) AF: 0.252 AC: 21164 AN: 84002

European-Finnish (FIN) AF: 0.273 AC: 14480 AN: 53012

Middle Eastern (MID) AF: 0.128 AC: 664 AN: 5200

European-Non Finnish (NFE) AF: 0.208 AC: 212261 AN: 1018726

Other (OTH) AF: 0.216 AC: 12322 AN: 56928

GnomAD4 genome AF: 0.248 AC: 37756 AN: 151962 Hom.: 5152 Cov.: 32 AF XY: 0.251 AC XY: 18624 AN XY: 74270

African (AFR) AF: 0.308 AC: 12755 AN: 41448

American (AMR) AF: 0.183 AC: 2790 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3466

East Asian (EAS) AF: 0.493 AC: 2537 AN: 5142

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4812

European-Finnish (FIN) AF: 0.288 AC: 3038 AN: 10552

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14092 AN: 67956

Other (OTH) AF: 0.216 AC: 455 AN: 2110

Alfa AF: 0.219 Hom.: 12363

Bravo AF: 0.245

Asia WGS AF: 0.404 AC: 1404 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	-0.82
CADD	Benign	4.7
DANN	Benign	0.37
PhyloP100		0.80
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2521206;

hg19: chr7-94039187;

COSMIC: COSV51953123;

COSMIC: COSV51953123;