rs150865922

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001844.5(COL2A1):c.1221C>T(p.Ser407=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S407S) has been classified as Uncertain significance.

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

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 -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/exons	MANE	UniProt
COL2A1	NM_001844.5 linkuse as main transcript	c.1221C>T	p.Ser407=	splice_region_variant, synonymous_variant	19/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8 linkuse as main transcript	c.1221C>T	p.Ser407=	splice_region_variant, synonymous_variant	19/54	1	NM_001844.5	P1	P02458-2
COL2A1	ENST00000337299.7 linkuse as main transcript	c.1014C>T	p.Ser338=	splice_region_variant, synonymous_variant	18/53	1			P02458-1
COL2A1	ENST00000493991.5 linkuse as main transcript	n.145C>T		splice_region_variant, non_coding_transcript_exon_variant	2/37	2

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

567

AN:

151936

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00435

AC XY:

576

AN XY:

132558

show subpopulations

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.:

Cov.:

AF XY:

0.00454

AC XY:

3293

AN XY:

725632

show subpopulations

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.:

Cov.:

AF XY:

0.00381

AC XY:

283

AN XY:

74308

show subpopulations

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.:

Bravo

AF:

0.00313

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COL2A1: BP4, BP7, BS1 -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Stickler syndrome type 1

Benign:1

Likely 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 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

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. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 28, 2020

- -

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

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