rs17073

Variant names:

• chr7-94406121-C-T
• rs17073
• NM_000089.4:c.541-129C>T

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.541-129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 926,898 control chromosomes in the GnomAD database, including 4,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (618 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3960 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.224
• Publications: 1 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=-0.81).
• BP6: Variant 7-94406121-C-T is Benign according to our data. Variant chr7-94406121-C-T is described in ClinVar as Benign. ClinVar VariationId is 1297451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 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.541-129C>T		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.541-129C>T		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.541-129C>T		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.541-129C>T		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.0815 AC: 12397 AN: 152120 Hom.: 617 Cov.: 32

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0980

GnomAD4 exome AF: 0.0938 AC: 72670 AN: 774660 Hom.: 3960 AF XY: 0.0911 AC XY: 36995 AN XY: 406014

African (AFR) AF: 0.0376 AC: 741 AN: 19720

American (AMR) AF: 0.0710 AC: 2531 AN: 35658

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2677 AN: 21258

East Asian (EAS) AF: 0.0000302 AC: 1 AN: 33144

South Asian (SAS) AF: 0.0267 AC: 1779 AN: 66564

European-Finnish (FIN) AF: 0.0800 AC: 3354 AN: 41938

Middle Eastern (MID) AF: 0.126 AC: 559 AN: 4432

European-Non Finnish (NFE) AF: 0.112 AC: 57392 AN: 514132

Other (OTH) AF: 0.0962 AC: 3636 AN: 37814

GnomAD4 genome AF: 0.0814 AC: 12393 AN: 152238 Hom.: 618 Cov.: 32 AF XY: 0.0778 AC XY: 5790 AN XY: 74430

African (AFR) AF: 0.0422 AC: 1751 AN: 41536

American (AMR) AF: 0.0875 AC: 1338 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4824

European-Finnish (FIN) AF: 0.0755 AC: 800 AN: 10602

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7583 AN: 68002

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.0828 Hom.: 284

Bravo AF: 0.0823

Asia WGS AF: 0.0150 AC: 51 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	-0.81
CADD	Benign	5.7
DANN	Benign	0.58
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17073; hg19: chr7-94035433;