7-94429175-C-T

Variant names:

• chr7-94429175-C-T
• rs74335369
• NM_000089.4:c.3712-13C>T

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.3712-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,603,358 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (214 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (212 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0750

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 7-94429175-C-T is Benign according to our data. Variant chr7-94429175-C-T is described in ClinVar as [Benign]. Clinvar id is 360971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94429175-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3712-13C>T		intron_variant	Intron 50 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.3712-13C>T		intron_variant	Intron 50 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000464916.1	n.760-13C>T		intron_variant	Intron 2 of 3	2
COL1A2	ENST00000481570.5	n.4493-13C>T		intron_variant	Intron 7 of 7	2

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4259 AN: 149488 Hom.: 213 Cov.: 31

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.0209

GnomAD3 exomes AF: 0.00825 AC: 2061 AN: 249728 Hom.: 95 AF XY: 0.00614 AC XY: 831 AN XY: 135248

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00972

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00327 AC: 4752 AN: 1453768 Hom.: 212 Cov.: 32 AF XY: 0.00285 AC XY: 2059 AN XY: 723438

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00957

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00653

GnomAD4 genome AF: 0.0285 AC: 4261 AN: 149590 Hom.: 214 Cov.: 31 AF XY: 0.0269 AC XY: 1962 AN XY: 72868

Gnomad4 AFR AF: 0.0994

Gnomad4 AMR AF: 0.00927

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00926

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.0207

Alfa AF: 0.0246 Hom.: 25

Bravo AF: 0.0330

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not specified Benign:1

Jun 06, 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. -

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. -

not provided Benign:1

Aug 23, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
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: rs74335369; hg19: chr7-94058487;