12-47985117-A-C

Variant names:

• chr12-47985117-A-C
• rs41317933
• NM_001844.5:c.1735-24T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001844.5(COL2A1):​c.1735-24T>G variant causes a intron change. The variant allele was found at a frequency of 0.0000126 in 1,430,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.74
• Publications: 0 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: 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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.48).

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.1735-24T>G		intron	N/A	NP_001835.3
	COL2A1	NM_033150.3		c.1528-24T>G		intron	N/A	NP_149162.2	P02458-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.1735-24T>G		intron	N/A	ENSP00000369889.3	P02458-2
	COL2A1	ENST00000337299.7	TSL:1	c.1528-24T>G		intron	N/A	ENSP00000338213.6	P02458-1
	COL2A1	ENST00000928357.1		c.1738-24T>G		intron	N/A	ENSP00000598416.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000126 AC: 18 AN: 1430410 Hom.: 0 Cov.: 26 AF XY: 0.0000126 AC XY: 9 AN XY: 712848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000609 AC: 2 AN: 32858

American (AMR) AF: 0.00 AC: 0 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1085762

Other (OTH) AF: 0.0000169 AC: 1 AN: 59334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		3.7
BranchPoint Hunter		5.0

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: rs41317933; hg19: chr12-48378900;