rs2472

Variant names:

• chr7-94422138-T-C
• rs2472
• NM_000089.4:c.2403+186T>C

Variant summary

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

The NM_000089.4(COL1A2):​c.2403+186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 526,010 control chromosomes in the GnomAD database, including 788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (201 hom., cov: 32)
  • Exomes 𝑓: 0.049 (587 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42

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 7-94422138-T-C is Benign according to our data. Variant chr7-94422138-T-C is described in ClinVar as [Benign]. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.2403+186T>C		intron_variant	Intron 39 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.2403+186T>C		intron_variant	Intron 39 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000497316.5	n.800+186T>C		intron_variant	Intron 8 of 8	2
COL1A2	ENST00000473573.5	n.*98T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6588 AN: 151964 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00933

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0340

GnomAD4 exome AF: 0.0490 AC: 18313 AN: 373932 Hom.: 587 AF XY: 0.0473 AC XY: 9170 AN XY: 193718

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0351

Gnomad4 ASJ exome AF: 0.0329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0433

Gnomad4 NFE exome AF: 0.0645

Gnomad4 OTH exome AF: 0.0450

GnomAD4 genome AF: 0.0433 AC: 6587 AN: 152078 Hom.: 201 Cov.: 32 AF XY: 0.0411 AC XY: 3056 AN XY: 74366

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0535 Hom.: 56

Bravo AF: 0.0419

Asia WGS AF: 0.00491 AC: 17 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	-0.85
CADD	Benign	6.1
DANN	Benign	0.56

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: rs2472; hg19: chr7-94051450;