chr7-94426787-A-G

Variant names:

• chr7-94426787-A-G
• rs7804898
• NM_000089.4:c.3106-221A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000089.4(COL1A2):​c.3106-221A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 626,086 control chromosomes in the GnomAD database, including 5,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1034 hom., cov: 31)
  • Exomes 𝑓: 0.13 (4378 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63
• Publications: 7 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 7-94426787-A-G is Benign according to our data. Variant chr7-94426787-A-G is described in ClinVar as Benign. ClinVar VariationId is 1221203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3106-221A>G		intron_variant	Intron 46 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.3106-221A>G		intron_variant	Intron 46 of 51	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16384 AN: 152064 Hom.: 1033 Cov.: 31

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0750

GnomAD4 exome AF: 0.129 AC: 60996 AN: 473904 Hom.: 4378 Cov.: 5 AF XY: 0.131 AC XY: 33179 AN XY: 253080

African (AFR) AF: 0.0612 AC: 785 AN: 12828

American (AMR) AF: 0.0716 AC: 1414 AN: 19752

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 998 AN: 14248

East Asian (EAS) AF: 0.137 AC: 4300 AN: 31498

South Asian (SAS) AF: 0.168 AC: 7713 AN: 45838

European-Finnish (FIN) AF: 0.184 AC: 5593 AN: 30420

Middle Eastern (MID) AF: 0.0514 AC: 106 AN: 2062

European-Non Finnish (NFE) AF: 0.128 AC: 37137 AN: 290236

Other (OTH) AF: 0.109 AC: 2950 AN: 27022

GnomAD4 genome AF: 0.108 AC: 16401 AN: 152182 Hom.: 1034 Cov.: 31 AF XY: 0.110 AC XY: 8148 AN XY: 74394

African (AFR) AF: 0.0595 AC: 2470 AN: 41536

American (AMR) AF: 0.0583 AC: 892 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0817 AC: 283 AN: 3466

East Asian (EAS) AF: 0.116 AC: 600 AN: 5178

South Asian (SAS) AF: 0.176 AC: 847 AN: 4816

European-Finnish (FIN) AF: 0.203 AC: 2148 AN: 10572

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8735 AN: 67994

Other (OTH) AF: 0.0780 AC: 165 AN: 2116

Alfa AF: 0.114 Hom.: 733

Bravo AF: 0.0942

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.83
PhyloP100		1.6
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: rs7804898; hg19: chr7-94056099;