12-47973403-G-A

Variant summary

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

The NM_001844.5(COL2A1):​c.*4C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,614,058 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 91 hom., cov: 32)
Exomes 𝑓: 0.0061 ( 122 hom. )

Consequence

COL2A1
NM_001844.5 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.46
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 12-47973403-G-A is Benign according to our data. Variant chr12-47973403-G-A is described in ClinVar as [Benign]. Clinvar id is 308902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47973403-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL2A1NM_001844.5 linkc.*4C>T 3_prime_UTR_variant Exon 54 of 54 ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL2A1ENST00000380518 linkc.*4C>T 3_prime_UTR_variant Exon 54 of 54 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000493991.5 linkn.3554C>T non_coding_transcript_exon_variant Exon 37 of 37 2
COL2A1ENST00000337299.7 linkc.*4C>T downstream_gene_variant 1 ENSP00000338213.6 P02458-1

Frequencies

GnomAD3 genomes
AF:
0.0213
AC:
3233
AN:
152050
Hom.:
90
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0624
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.0112
Gnomad ASJ
AF:
0.0300
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00249
Gnomad FIN
AF:
0.00113
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00451
Gnomad OTH
AF:
0.0163
GnomAD3 exomes
AF:
0.00967
AC:
2431
AN:
251494
Hom.:
52
AF XY:
0.00840
AC XY:
1142
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.0674
Gnomad AMR exome
AF:
0.00650
Gnomad ASJ exome
AF:
0.0342
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00307
Gnomad FIN exome
AF:
0.00148
Gnomad NFE exome
AF:
0.00511
Gnomad OTH exome
AF:
0.00945
GnomAD4 exome
AF:
0.00608
AC:
8891
AN:
1461890
Hom.:
122
Cov.:
31
AF XY:
0.00580
AC XY:
4220
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0667
Gnomad4 AMR exome
AF:
0.00693
Gnomad4 ASJ exome
AF:
0.0342
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00282
Gnomad4 FIN exome
AF:
0.00165
Gnomad4 NFE exome
AF:
0.00386
Gnomad4 OTH exome
AF:
0.0105
GnomAD4 genome
AF:
0.0213
AC:
3245
AN:
152168
Hom.:
91
Cov.:
32
AF XY:
0.0212
AC XY:
1581
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.0626
Gnomad4 AMR
AF:
0.0112
Gnomad4 ASJ
AF:
0.0300
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00229
Gnomad4 FIN
AF:
0.00113
Gnomad4 NFE
AF:
0.00451
Gnomad4 OTH
AF:
0.0161
Alfa
AF:
0.0113
Hom.:
10
Bravo
AF:
0.0255
Asia WGS
AF:
0.00635
AC:
22
AN:
3478
EpiCase
AF:
0.00605
EpiControl
AF:
0.00670

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Nov 22, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 06, 2018
Athena Diagnostics
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
Aug 26, 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. -

Stickler syndrome type 1 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. -

Type II Collagenopathies 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. -

Connective tissue disorder Benign:1
Nov 13, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
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
-0.32
CADD
Benign
12
DANN
Benign
0.87
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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.

Other links and lift over

dbSNP: rs41272773; hg19: chr12-48367186; API