7-94413962-A-G

Position:

• chr7-94413962-A-G

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.1665+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,605,380 control chromosomes in the GnomAD database, including 71,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6230 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65410 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.368

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=-0.82).
• BP6: Variant 7-94413962-A-G is Benign according to our data. Variant chr7-94413962-A-G is described in ClinVar as [Benign]. Clinvar id is 254954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94413962-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1665+15A>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.1665+15A>G		intron_variant		1	NM_000089.4	ENSP00000297268	P1
COL1A2	ENST00000488298.5	n.89+15A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43118 AN: 151852 Hom.: 6219 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.273 AC: 68577 AN: 250816 Hom.: 9786 AF XY: 0.273 AC XY: 36986 AN XY: 135516

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.231

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.297 AC: 432155 AN: 1453410 Hom.: 65410 Cov.: 33 AF XY: 0.296 AC XY: 214002 AN XY: 723568

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.284 AC: 43165 AN: 151970 Hom.: 6230 Cov.: 32 AF XY: 0.281 AC XY: 20870 AN XY: 74290

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.261

Alfa AF: 0.302 Hom.: 15095

Bravo AF: 0.277

Asia WGS AF: 0.218 AC: 758 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-danlos syndrome, arthrochalasia type, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.8
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: rs421587; hg19: chr7-94043274; COSMIC: COSV51952568; COSMIC: COSV51952568;