7-94427037-C-T

Variant names:

• chr7-94427037-C-T
• rs1800248
• NM_000089.4:c.3135C>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.3135C>T​(p.Gly1045Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,190 control chromosomes in the GnomAD database, including 13,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1033 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12496 hom.)
• Consequence: COL1A2 NM_000089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.800

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=-0.63).
• BP6: Variant 7-94427037-C-T is Benign according to our data. Variant chr7-94427037-C-T is described in ClinVar as [Benign]. Clinvar id is 254956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94427037-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3135C>T	p.Gly1045Gly	synonymous_variant	Exon 47 of 52	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.3135C>T	p.Gly1045Gly	synonymous_variant	Exon 47 of 52	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000481570.5	n.3585C>T		non_coding_transcript_exon_variant	Exon 5 of 8	2
COL1A2	ENST00000488121.1	n.51C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
COL1A2	ENST00000492110.1	n.255C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16311 AN: 152024 Hom.: 1032 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.0752

GnomAD3 exomes AF: 0.122 AC: 30569 AN: 251082 Hom.: 2132 AF XY: 0.126 AC XY: 17128 AN XY: 135680

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0793

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.127 AC: 185237 AN: 1461052 Hom.: 12496 Cov.: 34 AF XY: 0.128 AC XY: 93261 AN XY: 726850

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.0712

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.107 AC: 16329 AN: 152138 Hom.: 1033 Cov.: 32 AF XY: 0.109 AC XY: 8117 AN XY: 74396

Gnomad4 AFR AF: 0.0579

Gnomad4 AMR AF: 0.0580

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.0782

Alfa AF: 0.105 Hom.: 702

Bravo AF: 0.0936

Asia WGS AF: 0.151 AC: 523 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2016

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 17, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.63
CADD	Benign	5.2
DANN	Benign	0.55

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: rs1800248; hg19: chr7-94056349; COSMIC: COSV51955159; COSMIC: COSV51955159;