rs150865922

Variant names:

• chr12-47987611-G-A
• rs150865922
• NM_001844.5:c.1221C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47987611-G-A
• chr12-47987611-G-C
• chr12-47987611-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001844.5(COL2A1):​c.1221C>T​(p.Ser407Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,611,182 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (23 hom.)
• Consequence: COL2A1 NM_001844.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.001010
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.28

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-47987611-G-A is Benign according to our data. Variant chr12-47987611-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47987611-G-A is described in Lovd as [Benign]. Variant chr12-47987611-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00373 (567/152052) while in subpopulation NFE AF= 0.00496 (337/67988). AF 95% confidence interval is 0.00452. There are 3 homozygotes in gnomad4. There are 283 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 567 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1221C>T	p.Ser407Ser	splice_region_variant, synonymous_variant	Exon 19 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1221C>T	p.Ser407Ser	splice_region_variant, synonymous_variant	Exon 19 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.1014C>T	p.Ser338Ser	splice_region_variant, synonymous_variant	Exon 18 of 53	1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.145C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 37	2

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 151936 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00496

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00416 AC: 1017 AN: 244650 Hom.: 4 AF XY: 0.00435 AC XY: 576 AN XY: 132558

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000701

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00575

Gnomad OTH exome AF: 0.00336

GnomAD4 exome AF: 0.00467 AC: 6814 AN: 1459130 Hom.: 23 Cov.: 32 AF XY: 0.00454 AC XY: 3293 AN XY: 725632

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.000845

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000607

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.00514

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00373 AC: 567 AN: 152052 Hom.: 3 Cov.: 32 AF XY: 0.00381 AC XY: 283 AN XY: 74308

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00496

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00440 Hom.: 3

Bravo AF: 0.00313

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Oct 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL2A1: BP4, BP7, BS2 -

not specified Benign:4

Sep 19, 2017

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Stickler syndrome type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

Oct 28, 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	-0.28
CADD	Benign	7.1
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.068
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: rs150865922; hg19: chr12-48381394;