rs28417792

Variant names:

• chr7-94405377-C-T
• rs28417792
• NM_000089.4:c.486+125C>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.486+125C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 932,014 control chromosomes in the GnomAD database, including 6,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2973 hom., cov: 32)
  • Exomes 𝑓: 0.041 (3513 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.799
• Publications: 2 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=-0.81).
• BP6: Variant 7-94405377-C-T is Benign according to our data. Variant chr7-94405377-C-T is described in ClinVar as [Benign]. Clinvar id is 678457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.486+125C>T		intron_variant	Intron 10 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.486+125C>T		intron_variant	Intron 10 of 51	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18974 AN: 151576 Hom.: 2962 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.0655

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.0407 AC: 31764 AN: 780320 Hom.: 3513 AF XY: 0.0397 AC XY: 16038 AN XY: 404342

African (AFR) AF: 0.348 AC: 6264 AN: 18020

American (AMR) AF: 0.0655 AC: 1612 AN: 24598

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 304 AN: 19552

East Asian (EAS) AF: 0.343 AC: 11443 AN: 33410

South Asian (SAS) AF: 0.0525 AC: 3158 AN: 60128

European-Finnish (FIN) AF: 0.0314 AC: 1497 AN: 47740

Middle Eastern (MID) AF: 0.0286 AC: 108 AN: 3782

European-Non Finnish (NFE) AF: 0.00963 AC: 5161 AN: 536064

Other (OTH) AF: 0.0599 AC: 2217 AN: 37026

GnomAD4 genome AF: 0.125 AC: 19037 AN: 151694 Hom.: 2973 Cov.: 32 AF XY: 0.127 AC XY: 9398 AN XY: 74110

African (AFR) AF: 0.348 AC: 14367 AN: 41292

American (AMR) AF: 0.0772 AC: 1177 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3466

East Asian (EAS) AF: 0.354 AC: 1827 AN: 5162

South Asian (SAS) AF: 0.0649 AC: 312 AN: 4808

European-Finnish (FIN) AF: 0.0321 AC: 336 AN: 10480

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 729 AN: 67932

Other (OTH) AF: 0.108 AC: 227 AN: 2100

Alfa AF: 0.0812 Hom.: 184

Bravo AF: 0.140

Asia WGS AF: 0.238 AC: 828 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 19, 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	-0.81
CADD	Benign	4.5
DANN	Benign	0.48
PhyloP100		-0.80
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: rs28417792; hg19: chr7-94034689; COSMIC: COSV51958388;