7-94424688-T-C

Variant names:

• chr7-94424688-T-C
• rs441051
• NM_000089.4:c.2673+245T>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.2673+245T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 520,948 control chromosomes in the GnomAD database, including 153,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (44848 hom., cov: 32)
  • Exomes 𝑓: 0.77 (108983 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.36
• Publications: 19 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=-0.93).
• BP6: Variant 7-94424688-T-C is Benign according to our data. Variant chr7-94424688-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.2673+245T>C		intron_variant	Intron 41 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.2673+245T>C		intron_variant	Intron 41 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000481570.5	n.2218T>C		non_coding_transcript_exon_variant	Exon 1 of 8	2
COL1A2	ENST00000469732.1	n.456+245T>C		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116477 AN: 151978 Hom.: 44804 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.741

GnomAD4 exome AF: 0.766 AC: 282415 AN: 368852 Hom.: 108983 Cov.: 3 AF XY: 0.759 AC XY: 149214 AN XY: 196662

African (AFR) AF: 0.729 AC: 7766 AN: 10658

American (AMR) AF: 0.820 AC: 13254 AN: 16164

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 7853 AN: 11018

East Asian (EAS) AF: 0.929 AC: 21661 AN: 23326

South Asian (SAS) AF: 0.661 AC: 28426 AN: 43024

European-Finnish (FIN) AF: 0.793 AC: 16258 AN: 20502

Middle Eastern (MID) AF: 0.662 AC: 1075 AN: 1624

European-Non Finnish (NFE) AF: 0.769 AC: 170198 AN: 221414

Other (OTH) AF: 0.754 AC: 15924 AN: 21122

GnomAD4 genome AF: 0.766 AC: 116579 AN: 152096 Hom.: 44848 Cov.: 32 AF XY: 0.766 AC XY: 56975 AN XY: 74354

African (AFR) AF: 0.739 AC: 30641 AN: 41450

American (AMR) AF: 0.802 AC: 12261 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2475 AN: 3470

East Asian (EAS) AF: 0.908 AC: 4698 AN: 5172

South Asian (SAS) AF: 0.678 AC: 3270 AN: 4824

European-Finnish (FIN) AF: 0.796 AC: 8428 AN: 10584

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52301 AN: 67996

Other (OTH) AF: 0.743 AC: 1571 AN: 2114

Alfa AF: 0.768 Hom.: 167637

Bravo AF: 0.769

Asia WGS AF: 0.798 AC: 2774 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	-0.93
CADD	Benign	0.025
DANN	Benign	0.33
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs441051; hg19: chr7-94054000;