rs34026686

Variant names:

• chr7-94410975-G-A
• rs34026686
• NM_000089.4:c.1251+33G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-94410975-G-A
• chr7-94410975-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.1251+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,612,312 control chromosomes in the GnomAD database, including 30,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2375 hom., cov: 30)
  • Exomes 𝑓: 0.19 (27918 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.408
• 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):

• 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 7-94410975-G-A is Benign according to our data. Variant chr7-94410975-G-A is described in ClinVar as Benign. ClinVar VariationId is 674829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1251+33G>A		intron_variant	Intron 22 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.1251+33G>A		intron_variant	Intron 22 of 51	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25304 AN: 151602 Hom.: 2369 Cov.: 30

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0728

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0847

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.185 AC: 46502 AN: 251272 AF XY: 0.178

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0990

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.190 AC: 278089 AN: 1460598 Hom.: 27918 Cov.: 34 AF XY: 0.187 AC XY: 135776 AN XY: 726660

African (AFR) AF: 0.104 AC: 3480 AN: 33460

American (AMR) AF: 0.348 AC: 15558 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4661 AN: 26124

East Asian (EAS) AF: 0.102 AC: 4034 AN: 39694

South Asian (SAS) AF: 0.107 AC: 9243 AN: 86248

European-Finnish (FIN) AF: 0.107 AC: 5711 AN: 53178

Middle Eastern (MID) AF: 0.150 AC: 864 AN: 5766

European-Non Finnish (NFE) AF: 0.201 AC: 223544 AN: 1111044

Other (OTH) AF: 0.182 AC: 10994 AN: 60374

GnomAD4 genome AF: 0.167 AC: 25330 AN: 151714 Hom.: 2375 Cov.: 30 AF XY: 0.165 AC XY: 12206 AN XY: 74090

African (AFR) AF: 0.108 AC: 4469 AN: 41356

American (AMR) AF: 0.296 AC: 4513 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.111 AC: 573 AN: 5150

South Asian (SAS) AF: 0.106 AC: 506 AN: 4786

European-Finnish (FIN) AF: 0.0847 AC: 889 AN: 10502

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13307 AN: 67912

Other (OTH) AF: 0.186 AC: 391 AN: 2106

Alfa AF: 0.180 Hom.: 916

Bravo AF: 0.182

Asia WGS AF: 0.109 AC: 380 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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.59
DANN	Benign	0.42
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs34026686; hg19: chr7-94040287; COSMIC: COSV51955089; COSMIC: COSV51955089;