rs42526

Variant names:

• chr7-94416264-G-A
• rs42526
• NM_000089.4:c.1765-141G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-94416264-G-A
• chr7-94416264-G-C
• chr7-94416264-G-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.1765-141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 680,802 control chromosomes in the GnomAD database, including 169,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34060 hom., cov: 33)
  • Exomes 𝑓: 0.71 (135150 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.90
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-94416264-G-A is Benign according to our data. Variant chr7-94416264-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1765-141G>A		intron_variant	Intron 30 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.1765-141G>A		intron_variant	Intron 30 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000473573.5	n.102-141G>A		intron_variant	Intron 2 of 10	2
COL1A2	ENST00000488298.5	n.189-141G>A		intron_variant	Intron 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100302 AN: 152042 Hom.: 34043 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.710 AC: 375484 AN: 528642 Hom.: 135150 AF XY: 0.704 AC XY: 194751 AN XY: 276472

African (AFR) AF: 0.487 AC: 6733 AN: 13836

American (AMR) AF: 0.735 AC: 15895 AN: 21638

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 9924 AN: 15098

East Asian (EAS) AF: 0.584 AC: 18416 AN: 31516

South Asian (SAS) AF: 0.584 AC: 27337 AN: 46784

European-Finnish (FIN) AF: 0.751 AC: 29104 AN: 38774

Middle Eastern (MID) AF: 0.580 AC: 1251 AN: 2156

European-Non Finnish (NFE) AF: 0.749 AC: 247341 AN: 330300

Other (OTH) AF: 0.683 AC: 19483 AN: 28540

GnomAD4 genome AF: 0.660 AC: 100358 AN: 152160 Hom.: 34060 Cov.: 33 AF XY: 0.658 AC XY: 48912 AN XY: 74380

African (AFR) AF: 0.495 AC: 20520 AN: 41492

American (AMR) AF: 0.716 AC: 10948 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2274 AN: 3472

East Asian (EAS) AF: 0.540 AC: 2790 AN: 5164

South Asian (SAS) AF: 0.593 AC: 2861 AN: 4826

European-Finnish (FIN) AF: 0.751 AC: 7938 AN: 10576

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50875 AN: 68016

Other (OTH) AF: 0.630 AC: 1333 AN: 2116

Alfa AF: 0.617 Hom.: 2284

Bravo AF: 0.652

Asia WGS AF: 0.550 AC: 1911 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 23, 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	-0.85
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		1.9
Mutation Taster		=99/1	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: rs42526; hg19: chr7-94045576;