rs10875716

Variant names:

• chr12-47995240-C-T
• rs10875716
• NM_001844.5:c.762+15G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.762+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,606,170 control chromosomes in the GnomAD database, including 95,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6384 hom., cov: 32)
  • Exomes 𝑓: 0.34 (89160 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.133

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-47995240-C-T is Benign according to our data. Variant chr12-47995240-C-T is described in ClinVar as [Benign]. Clinvar id is 258244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47995240-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.762+15G>A		intron_variant	Intron 11 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.762+15G>A		intron_variant	Intron 11 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.555+15G>A		intron_variant	Intron 10 of 52	1		ENSP00000338213.6

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39032 AN: 152092 Hom.: 6382 Cov.: 32

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.291 AC: 73255 AN: 251384 Hom.: 12505 AF XY: 0.300 AC XY: 40781 AN XY: 135870

Gnomad AFR exome AF: 0.0608

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.00832

Gnomad SAS exome AF: 0.293

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.376

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.340 AC: 494035 AN: 1453958 Hom.: 89160 Cov.: 31 AF XY: 0.340 AC XY: 246005 AN XY: 723830

Gnomad4 AFR exome AF: 0.0555

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.365

Gnomad4 EAS exome AF: 0.00474

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.256 AC: 39039 AN: 152212 Hom.: 6384 Cov.: 32 AF XY: 0.254 AC XY: 18873 AN XY: 74432

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.375

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.273

Alfa AF: 0.308 Hom.: 1848

Bravo AF: 0.241

Asia WGS AF: 0.163 AC: 570 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
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: rs10875716; hg19: chr12-48389023;