dbSNP rs141423593: COL2A1:p.Gly858Gly (chr12-47980605-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001844.5(COL2A1):c.2574C>T(p.Gly858Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,612,844 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 17 hom. )

Consequence

COL2A1
NM_001844.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: -4.36

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

achondrogenesis type II
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
COL2A1-related spondyloepiphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dysplasia of the proximal femoral epiphyses
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Kniest dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
platyspondylic dysplasia, Torrance type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
spondyloepimetaphyseal dysplasia, Strudwick type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
spondyloepiphyseal dysplasia congenita
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
spondyloepiphyseal dysplasia with metatarsal shortening
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
spondylometaphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spondyloperipheral dysplasia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Stickler syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Illumina
Stickler syndrome, type I, nonsyndromic ocular
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
avascular necrosis of femoral head, primary, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Legg-Calve-Perthes disease
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
otospondylomegaepiphyseal dysplasia, autosomal recessive
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
spondyloepiphyseal dysplasia, Stanescu type
Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal dominant rhegmatogenous retinal detachment
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dysspondyloenchondromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial avascular necrosis of femoral head
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypochondrogenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple epiphyseal dysplasia, Beighton type
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
spondylometaphyseal dysplasia, Schmidt type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
otospondylomegaepiphyseal dysplasia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
vitreoretinopathy with phalangeal epiphyseal dysplasia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

COL2A1 links:

LOC105369752 (HGNC:):

LOC105369752 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 12-47980605-G-A is Benign according to our data. Variant chr12-47980605-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252593.

BP7

Synonymous conserved (PhyloP=-4.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00267 (407/152256) while in subpopulation NFE AF = 0.00434 (295/67996). AF 95% confidence interval is 0.00393. There are 1 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	NM_001844.5	MANE Select	c.2574C>T	p.Gly858Gly	synonymous	Exon 39 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.2367C>T	p.Gly789Gly	synonymous	Exon 38 of 53	NP_149162.2	P02458-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.2574C>T	p.Gly858Gly	synonymous	Exon 39 of 54	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7	TSL:1	c.2367C>T	p.Gly789Gly	synonymous	Exon 38 of 53	ENSP00000338213.6	P02458-1
COL2A1	ENST00000928357.1		c.2577C>T	p.Gly859Gly	synonymous	Exon 39 of 54	ENSP00000598416.1

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

407

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00231

AC:

572

AN:

247208

AF XY:

0.00237

show subpopulations

Gnomad AFR exome

AF:

0.000569

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00599

Gnomad NFE exome

AF:

0.00340

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00356

AC:

5205

AN:

1460588

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2470

AN XY:

726458

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33470

American (AMR)

AF:

0.000941

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.000460

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000338

AC:

AN:

85920

European-Finnish (FIN)

AF:

0.00600

AC:

318

AN:

53014

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00409

AC:

4542

AN:

1111654

Other (OTH)

AF:

0.00404

AC:

244

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

297

594

890

1187

1484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00267

AC:

407

AN:

152256

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

188

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41554

American (AMR)

AF:

0.00124

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00434

AC:

295

AN:

67996

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.00203

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00285

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Connective tissue disorder (1)

Stickler syndrome type 1 (1)

Type II Collagenopathies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.034

(source)

DANN

Benign

0.54

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over