7-94409622-C-T

Variant names:

• chr7-94409622-C-T
• rs42518
• NM_000089.4:c.936+14C>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.936+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,613,822 control chromosomes in the GnomAD database, including 490,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50549 hom., cov: 32)
  • Exomes 𝑓: 0.77 (440367 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.993

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=-0.86).
• BP6: Variant 7-94409622-C-T is Benign according to our data. Variant chr7-94409622-C-T is described in ClinVar as [Benign]. Clinvar id is 254957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94409622-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.936+14C>T		intron_variant	Intron 18 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.936+14C>T		intron_variant	Intron 18 of 51	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123437 AN: 152070 Hom.: 50498 Cov.: 32

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.782 AC: 196752 AN: 251478 Hom.: 77699 AF XY: 0.771 AC XY: 104728 AN XY: 135910

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.824

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.909

Gnomad SAS exome AF: 0.663

Gnomad FIN exome AF: 0.794

Gnomad NFE exome AF: 0.772

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.774 AC: 1131898 AN: 1461634 Hom.: 440367 Cov.: 53 AF XY: 0.770 AC XY: 559718 AN XY: 727142

Gnomad4 AFR exome AF: 0.898

Gnomad4 AMR exome AF: 0.822

Gnomad4 ASJ exome AF: 0.687

Gnomad4 EAS exome AF: 0.938

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.789

Gnomad4 NFE exome AF: 0.774

Gnomad4 OTH exome AF: 0.764

GnomAD4 genome AF: 0.812 AC: 123547 AN: 152188 Hom.: 50549 Cov.: 32 AF XY: 0.810 AC XY: 60244 AN XY: 74386

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.804

Gnomad4 ASJ AF: 0.681

Gnomad4 EAS AF: 0.914

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.791

Gnomad4 NFE AF: 0.775

Gnomad4 OTH AF: 0.775

Alfa AF: 0.772 Hom.: 26585

Bravo AF: 0.821

Asia WGS AF: 0.801 AC: 2786 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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. -

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2 Benign:2

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Osteogenesis imperfecta type III Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta with normal sclerae, dominant form Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta, perinatal lethal Benign:1

Jul 22, 2021

Genome-Nilou Lab

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 04, 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	-0.86
CADD	Benign	0.28
DANN	Benign	0.31

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: rs42518; hg19: chr7-94038934; COSMIC: COSV99800215; COSMIC: COSV99800215;