rs406226

Positions:

• chr7-94404488-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000297268.11(COL1A2):​c.280-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,557,980 control chromosomes in the GnomAD database, including 29,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2533 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26752 hom.)
• Consequence: COL1A2 ENST00000297268.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.60

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-94404488-A-G is Benign according to our data. Variant chr7-94404488-A-G is described in ClinVar as [Benign]. Clinvar id is 674810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.280-68A>G		intron_variant		ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.280-68A>G		intron_variant		1	NM_000089.4	ENSP00000297268	P1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26832 AN: 152126 Hom.: 2525 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.190 AC: 266858 AN: 1405736 Hom.: 26752 AF XY: 0.186 AC XY: 130764 AN XY: 702610

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0989

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.176 AC: 26863 AN: 152244 Hom.: 2533 Cov.: 32 AF XY: 0.173 AC XY: 12910 AN XY: 74454

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0785

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.188

Alfa AF: 0.193 Hom.: 4905

Bravo AF: 0.193

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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	0.14
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs406226; hg19: chr7-94033800;