7-94426621-T-C

Variant names:

• chr7-94426621-T-C
• rs13240759
• NM_000089.4:c.3105+91T>C

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.3105+91T>C 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 963,196 control chromosomes in the GnomAD database, including 18,037 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2701 hom., cov: 32)
  • Exomes 𝑓: 0.19 (15336 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.336
• Publications: 12 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=-0.86).
• BP6: Variant 7-94426621-T-C is Benign according to our data. Variant chr7-94426621-T-C is described in ClinVar as Benign. ClinVar VariationId is 674832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3105+91T>C		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.3105+91T>C		intron_variant	Intron 46 of 51	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27873 AN: 152028 Hom.: 2696 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0893

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.189 AC: 152984 AN: 811050 Hom.: 15336 Cov.: 11 AF XY: 0.184 AC XY: 77754 AN XY: 422056

African (AFR) AF: 0.174 AC: 3565 AN: 20440

American (AMR) AF: 0.339 AC: 11869 AN: 34980

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 3787 AN: 21540

East Asian (EAS) AF: 0.107 AC: 3547 AN: 33104

South Asian (SAS) AF: 0.110 AC: 7407 AN: 67268

European-Finnish (FIN) AF: 0.111 AC: 5401 AN: 48590

Middle Eastern (MID) AF: 0.150 AC: 678 AN: 4510

European-Non Finnish (NFE) AF: 0.202 AC: 109527 AN: 541950

Other (OTH) AF: 0.186 AC: 7203 AN: 38668

GnomAD4 genome AF: 0.183 AC: 27899 AN: 152146 Hom.: 2701 Cov.: 32 AF XY: 0.180 AC XY: 13396 AN XY: 74388

African (AFR) AF: 0.171 AC: 7080 AN: 41498

American (AMR) AF: 0.295 AC: 4499 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3472

East Asian (EAS) AF: 0.129 AC: 668 AN: 5172

South Asian (SAS) AF: 0.109 AC: 526 AN: 4826

European-Finnish (FIN) AF: 0.0893 AC: 947 AN: 10606

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.193 AC: 13104 AN: 67988

Other (OTH) AF: 0.194 AC: 411 AN: 2116

Alfa AF: 0.186 Hom.: 909

Bravo AF: 0.200

Asia WGS AF: 0.120 AC: 418 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	-0.86
CADD	Benign	2.8
DANN	Benign	0.29
PhyloP100		-0.34
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: rs13240759; hg19: chr7-94055933; COSMIC: COSV51955109; COSMIC: COSV51955109;