rs34392760

Variant names:

• chr12-47997874-T-A
• rs34392760
• NM_001844.5:c.426A>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.426A>T​(p.Glu142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,614,054 control chromosomes in the GnomAD database, including 2,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (149 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1878 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.249
• Publications: 22 publications found

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: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Kniest dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• platyspondylic dysplasia, Torrance type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• spondyloepimetaphyseal dysplasia, Strudwick type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• spondyloepiphyseal dysplasia congenita

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia with metatarsal shortening

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• spondylometaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondyloperipheral dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Stickler syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
• Stickler syndrome, type I, nonsyndromic ocular

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Orphanet
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia, Stanescu type

  Inheritance: 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the COL2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. Gene score misZ: 3.2926 (above the threshold of 3.09). Trascript score misZ: 5.3726 (above the threshold of 3.09). GenCC associations: The gene is linked to vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, Kniest dysplasia, Stickler syndrome type 1, platyspondylic dysplasia, Torrance type, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia, Stanescu type, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia congenita, multiple epiphyseal dysplasia, Beighton type, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, autosomal dominant rhegmatogenous retinal detachment, spondylometaphyseal dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, familial avascular necrosis of femoral head, dysspondyloenchondromatosis, spondylometaphyseal dysplasia, Schmidt type, hypochondrogenesis, otospondylomegaepiphyseal dysplasia, autosomal recessive, otospondylomegaepiphyseal dysplasia, avascular necrosis of femoral head, primary, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039563477).
• BP6: Variant 12-47997874-T-A is Benign according to our data. Variant chr12-47997874-T-A is described in ClinVar as Benign. ClinVar VariationId is 258239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	NM_001844.5	MANE Select	c.426A>T	p.Glu142Asp	missense	Exon 6 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.219A>T	p.Glu73Asp	missense	Exon 5 of 53	NP_149162.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.426A>T	p.Glu142Asp	missense	Exon 6 of 54	ENSP00000369889.3
	COL2A1	ENST00000337299.7	TSL:1	c.219A>T	p.Glu73Asp	missense	Exon 5 of 53	ENSP00000338213.6
	COL2A1	ENST00000474996.6	TSL:3	n.664A>T		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5565 AN: 152206 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0376 AC: 9443 AN: 251170 AF XY: 0.0378

Gnomad AFR exome AF: 0.00819

Gnomad AMR exome AF: 0.0268

Gnomad ASJ exome AF: 0.0695

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0481 AC: 70318 AN: 1461730 Hom.: 1878 Cov.: 33 AF XY: 0.0473 AC XY: 34426 AN XY: 727156

African (AFR) AF: 0.00824 AC: 276 AN: 33480

American (AMR) AF: 0.0280 AC: 1253 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1858 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0132 AC: 1141 AN: 86258

European-Finnish (FIN) AF: 0.0289 AC: 1542 AN: 53322

Middle Eastern (MID) AF: 0.0551 AC: 317 AN: 5748

European-Non Finnish (NFE) AF: 0.0550 AC: 61204 AN: 1111972

Other (OTH) AF: 0.0451 AC: 2723 AN: 60390

GnomAD4 genome AF: 0.0365 AC: 5563 AN: 152324 Hom.: 149 Cov.: 33 AF XY: 0.0339 AC XY: 2525 AN XY: 74492

African (AFR) AF: 0.00914 AC: 380 AN: 41574

American (AMR) AF: 0.0409 AC: 626 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4828

European-Finnish (FIN) AF: 0.0232 AC: 247 AN: 10626

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3864 AN: 68020

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0520 Hom.: 93

Bravo AF: 0.0359

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0623 AC: 240

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0530 AC: 456

ExAC AF: 0.0381 AC: 4622

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0569

EpiControl AF: 0.0616

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Stickler syndrome type 1 (1)
-	-	1	Type II Collagenopathies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.025	N
PhyloP100		0.25
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.29
Sift	Benign	0.49	T
Sift4G	Benign	0.72	T
Polyphen		0.0020	B
Vest4		0.061
MutPred		0.16		Loss of methylation at K140 (P = 0.1224)
MPC		0.11
ClinPred		0.0062	T
GERP RS		3.9
Varity_R		0.15
gMVP		0.20
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34392760; hg19: chr12-48391657;