rs2301643

chr7-94414181-G-Achr7-94414181-G-Cchr7-94414181-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000089.4(COL1A2):c.1666-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,603,114 control chromosomes in the GnomAD database, including 28,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2416 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25882 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-94414181-G-A is Benign according to our data. Variant chr7-94414181-G-A is described in ClinVar as [Benign]. Clinvar id is 674830.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.1666-41G>A		intron_variant		ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.1666-41G>A		intron_variant		1	NM_000089.4	P1
COL1A2	ENST00000488298.5	n.90-41G>A		intron_variant, non_coding_transcript_variant		2
COL1A2	ENST00000473573.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26069 AN: 151968 Hom.: 2412 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0854

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.183 AC: 45784 AN: 250562 Hom.: 4986 AF XY: 0.175 AC XY: 23680 AN XY: 135416

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.0993

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.184 AC: 267454 AN: 1451028 Hom.: 25882 Cov.: 30 AF XY: 0.181 AC XY: 130814 AN XY: 722608

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.172 AC: 26091 AN: 152086 Hom.: 2416 Cov.: 32 AF XY: 0.169 AC XY: 12537 AN XY: 74344

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0854

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.185

Alfa AF: 0.124 Hom.: 259

Bravo AF: 0.187

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 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	-0.84
Cadd	Benign	7.5
Dann	Benign	0.63

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: rs2301643; hg19: chr7-94043493; COSMIC: COSV51955100; COSMIC: COSV51955100;