rs1800238

chr7-94417738-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000089.4(COL1A2):c.1878G>T(p.Val626=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,595,068 control chromosomes in the GnomAD database, including 3,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (435 hom., cov: 32)
  • Exomes 𝑓: 0.024 (3012 hom.)
• Consequence: COL1A2 NM_000089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.290

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-94417738-G-T is Benign according to our data. Variant chr7-94417738-G-T is described in ClinVar as [Benign]. Clinvar id is 360958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94417738-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.1878G>T	p.Val626=	synonymous_variant	32/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.1878G>T	p.Val626=	synonymous_variant	32/52	1	NM_000089.4	P1
COL1A2	ENST00000473573.5	n.215G>T		non_coding_transcript_exon_variant	4/11	2
COL1A2	ENST00000497316.5	n.275G>T		non_coding_transcript_exon_variant	1/9	2
COL1A2	ENST00000461525.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4827 AN: 152102 Hom.: 434 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00935

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0520 AC: 11443 AN: 219926 Hom.: 1209 AF XY: 0.0494 AC XY: 5805 AN XY: 117588

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0664

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.363

Gnomad SAS exome AF: 0.0530

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0239 AC: 34438 AN: 1442848 Hom.: 3012 Cov.: 31 AF XY: 0.0243 AC XY: 17376 AN XY: 715382

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.0607

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.0534

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.00809

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.0318 AC: 4836 AN: 152220 Hom.: 435 Cov.: 32 AF XY: 0.0357 AC XY: 2660 AN XY: 74442

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.0472

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.0662

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.00934

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0131 Hom.: 25

Bravo AF: 0.0345

Asia WGS AF: 0.226 AC: 785 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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	Athena Diagnostics	Jul 28, 2017	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.8
Dann	Benign	0.51

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: rs1800238; hg19: chr7-94047050; COSMIC: COSV51969140; COSMIC: COSV51969140;