NM_000089.4:c.2673+245T>A

Variant names:

• chr7-94424688-T-A
• rs441051
• NM_000089.4:c.2673+245T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000089.4(COL1A2):​c.2673+245T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000271 in 369,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.36
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000271 AC: 1 AN: 369352 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 196902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10668

American (AMR) AF: 0.00 AC: 0 AN: 16186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11040

East Asian (EAS) AF: 0.00 AC: 0 AN: 23336

South Asian (SAS) AF: 0.00 AC: 0 AN: 43062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1624

European-Non Finnish (NFE) AF: 0.00000451 AC: 1 AN: 221764

Other (OTH) AF: 0.00 AC: 0 AN: 21146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.020
DANN	Benign	0.47
PhyloP100		-2.4

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: rs441051; hg19: chr7-94054000;