chr7-94410821-T-A

Variant names:

• chr7-94410821-T-A
• rs389328
• NM_000089.4:c.1198-68T>A

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.1198-68T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 1,548,134 control chromosomes in the GnomAD database, including 579,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60918 hom., cov: 30)
  • Exomes 𝑓: 0.86 (518312 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0400
• Publications: 14 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):

• Ehlers-Danlos syndrome, arthrochalasia type, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, 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, G2P, ClinGen
• osteogenesis imperfecta type 3

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

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-94410821-T-A is Benign according to our data. Variant chr7-94410821-T-A is described in ClinVar as Benign. ClinVar VariationId is 674812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.1198-68T>A		intron	N/A	NP_000080.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.1198-68T>A		intron	N/A	ENSP00000297268.6
	COL1A2	ENST00000959377.1		c.1198-68T>A		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.1198-68T>A		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135727 AN: 152026 Hom.: 60863 Cov.: 30

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.876

GnomAD4 exome AF: 0.861 AC: 1202093 AN: 1395990 Hom.: 518312 AF XY: 0.860 AC XY: 600674 AN XY: 698584

African (AFR) AF: 0.966 AC: 31037 AN: 32134

American (AMR) AF: 0.888 AC: 39570 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 20090 AN: 25768

East Asian (EAS) AF: 0.987 AC: 38840 AN: 39356

South Asian (SAS) AF: 0.836 AC: 70695 AN: 84560

European-Finnish (FIN) AF: 0.865 AC: 46046 AN: 53262

Middle Eastern (MID) AF: 0.810 AC: 4480 AN: 5534

European-Non Finnish (NFE) AF: 0.856 AC: 901268 AN: 1052602

Other (OTH) AF: 0.860 AC: 50067 AN: 58202

GnomAD4 genome AF: 0.893 AC: 135842 AN: 152144 Hom.: 60918 Cov.: 30 AF XY: 0.891 AC XY: 66296 AN XY: 74376

African (AFR) AF: 0.963 AC: 39997 AN: 41514

American (AMR) AF: 0.882 AC: 13477 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2697 AN: 3466

East Asian (EAS) AF: 0.978 AC: 5077 AN: 5190

South Asian (SAS) AF: 0.850 AC: 4089 AN: 4810

European-Finnish (FIN) AF: 0.866 AC: 9159 AN: 10582

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58411 AN: 67990

Other (OTH) AF: 0.878 AC: 1851 AN: 2108

Alfa AF: 0.873 Hom.: 7272

Bravo AF: 0.898

Asia WGS AF: 0.917 AC: 3188 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.88
CADD	Benign	0.48
DANN	Benign	0.34
PhyloP100		0.040
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: rs389328; hg19: chr7-94040133;