Genetic Variant COL2A1:c.1735-24T>C (chr12-47985117-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001844.5(COL2A1):c.1735-24T>C variant causes a intron change. The variant allele was found at a frequency of 0.063 in 1,582,242 control chromosomes in the GnomAD database, including 3,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.051 ( 247 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3405 hom. )

Consequence

COL2A1
NM_001844.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.74

Variant links:

Genes affected

COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

COL2A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 12-47985117-A-G is Benign according to our data. Variant chr12-47985117-A-G is described in ClinVar as [Benign]. Clinvar id is 258216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.1735-24T>C		intron_variant	Intron 26 of 53	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL2A1	ENST00000380518.8 link	c.1735-24T>C	intron_variant	Intron 26 of 53	1	NM_001844.5	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7 link	c.1528-24T>C	intron_variant	Intron 25 of 52	1		ENSP00000338213.6	P02458-1
COL2A1	ENST00000493991.5 link	n.659-24T>C	intron_variant	Intron 9 of 36	2

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7685

AN:

152078

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.0861

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0735

Gnomad OTH

AF:

0.0455

GnomAD3 exomes

AF:

0.0482

AC:

11495

AN:

238680

Hom.:

394

AF XY:

0.0476

AC XY:

6174

AN XY:

129650

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.000282

Gnomad SAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.0889

Gnomad NFE exome

AF:

0.0740

Gnomad OTH exome

AF:

0.0500

GnomAD4 exome

AF:

0.0643

AC:

91991

AN:

1430046

Hom.:

3405

Cov.:

AF XY:

0.0628

AC XY:

44728

AN XY:

712670

show subpopulations

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.0210

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.000432

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.0879

Gnomad4 NFE exome

AF:

0.0747

Gnomad4 OTH exome

AF:

0.0547

GnomAD4 genome

AF:

0.0505

AC:

7691

AN:

152196

Hom.:

247

Cov.:

AF XY:

0.0500

AC XY:

3717

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0270

Gnomad4 AMR

AF:

0.0291

Gnomad4 ASJ

AF:

0.0113

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.0861

Gnomad4 NFE

AF:

0.0735

Gnomad4 OTH

AF:

0.0450

Alfa

AF:

0.0674

Hom.:

175

Bravo

AF:

0.0436

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.43

CADD

Benign

DANN

Benign

0.76

BranchPoint Hunter

5.0

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