rs42517

Variant names:

• chr7-94407722-A-G
• rs42517
• NM_000089.4:c.595-125A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-94407722-A-G
• chr7-94407722-A-C

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.595-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 795,514 control chromosomes in the GnomAD database, including 24,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3664 hom., cov: 32)
  • Exomes 𝑓: 0.25 (20345 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.470
• Publications: 10 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=-0.73).
• BP6: Variant 7-94407722-A-G is Benign according to our data. Variant chr7-94407722-A-G is described in ClinVar as Benign. ClinVar VariationId is 1227903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.254 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.595-125A>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.595-125A>G		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.595-125A>G		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.595-125A>G		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29879 AN: 152050 Hom.: 3667 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.246 AC: 158576 AN: 643346 Hom.: 20345 AF XY: 0.248 AC XY: 83756 AN XY: 338124

African (AFR) AF: 0.0536 AC: 839 AN: 15654

American (AMR) AF: 0.166 AC: 4315 AN: 25992

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 3953 AN: 17478

East Asian (EAS) AF: 0.263 AC: 8137 AN: 30886

South Asian (SAS) AF: 0.262 AC: 14436 AN: 55106

European-Finnish (FIN) AF: 0.323 AC: 14310 AN: 44258

Middle Eastern (MID) AF: 0.185 AC: 424 AN: 2298

European-Non Finnish (NFE) AF: 0.250 AC: 104935 AN: 419986

Other (OTH) AF: 0.228 AC: 7227 AN: 31688

GnomAD4 genome AF: 0.196 AC: 29860 AN: 152168 Hom.: 3664 Cov.: 32 AF XY: 0.201 AC XY: 14917 AN XY: 74360

African (AFR) AF: 0.0577 AC: 2399 AN: 41572

American (AMR) AF: 0.190 AC: 2897 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 776 AN: 3472

East Asian (EAS) AF: 0.265 AC: 1373 AN: 5176

South Asian (SAS) AF: 0.259 AC: 1249 AN: 4824

European-Finnish (FIN) AF: 0.333 AC: 3511 AN: 10546

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16990 AN: 67972

Other (OTH) AF: 0.184 AC: 390 AN: 2114

Alfa AF: 0.155 Hom.: 1167

Bravo AF: 0.178

Asia WGS AF: 0.226 AC: 783 AN: 3474

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	-0.73
CADD	Benign	8.4
DANN	Benign	0.85
PhyloP100		-0.47
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: rs42517; hg19: chr7-94037034;