rs74335369

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000089.4(COL1A2):c.3712-13C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0750

Variant links:

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]

COL1A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
COL1A2	NM_000089.4 linkuse as main transcript	c.3712-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
COL1A2	ENST00000297268.11 linkuse as main transcript	c.3712-13C>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000089.4	P1
COL1A2	ENST00000464916.1 linkuse as main transcript	n.760-13C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2
COL1A2	ENST00000481570.5 linkuse as main transcript	n.4493-13C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4259

AN:

149488

Hom.:

213

Cov.:

show subpopulations

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.:

AF XY:

0.00614

AC XY:

831

AN XY:

135248

show subpopulations

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.:

AF XY:

0.00285

AC XY:

2059

AN XY:

723438

show subpopulations

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.:

AF XY:

0.0269

AC XY:

1962

AN XY:

72868

show subpopulations

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.:

Bravo

AF:

0.0330

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 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. -

Ehlers-danlos syndrome, arthrochalasia type, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 23, 2017

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over