rs1793953

Variant names:

• chr12-47999743-G-A
• rs1793953
• NM_001844.5:c.292+176C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47999743-G-A
• chr12-47999743-G-C
• chr12-47999743-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.292+176C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 614,208 control chromosomes in the GnomAD database, including 114,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23292 hom., cov: 27)
  • Exomes 𝑓: 0.62 (91489 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.09
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-47999743-G-A is Benign according to our data. Variant chr12-47999743-G-A is described in ClinVar as Benign. ClinVar VariationId is 677851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.667 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.292+176C>T		intron	N/A	NP_001835.3
	COL2A1	NM_033150.3		c.86-1312C>T		intron	N/A	NP_149162.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.292+176C>T		intron	N/A	ENSP00000369889.3
	COL2A1	ENST00000337299.7	TSL:1	c.86-1312C>T		intron	N/A	ENSP00000338213.6
	COL2A1	ENST00000490609.2	TSL:2	n.701C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.530 AC: 79186 AN: 149516 Hom.: 23292 Cov.: 27

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.593

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.562

GnomAD4 exome AF: 0.620 AC: 287828 AN: 464566 Hom.: 91489 Cov.: 4 AF XY: 0.621 AC XY: 153067 AN XY: 246480

African (AFR) AF: 0.257 AC: 3307 AN: 12880

American (AMR) AF: 0.487 AC: 12115 AN: 24896

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 9833 AN: 14628

East Asian (EAS) AF: 0.393 AC: 11526 AN: 29328

South Asian (SAS) AF: 0.597 AC: 28925 AN: 48438

European-Finnish (FIN) AF: 0.587 AC: 17272 AN: 29426

Middle Eastern (MID) AF: 0.621 AC: 1256 AN: 2022

European-Non Finnish (NFE) AF: 0.677 AC: 187362 AN: 276656

Other (OTH) AF: 0.617 AC: 16232 AN: 26292

GnomAD4 genome AF: 0.529 AC: 79222 AN: 149642 Hom.: 23292 Cov.: 27 AF XY: 0.527 AC XY: 38407 AN XY: 72876

African (AFR) AF: 0.252 AC: 10194 AN: 40390

American (AMR) AF: 0.554 AC: 8239 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2389 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2224 AN: 4942

South Asian (SAS) AF: 0.589 AC: 2775 AN: 4710

European-Finnish (FIN) AF: 0.591 AC: 6025 AN: 10192

Middle Eastern (MID) AF: 0.597 AC: 173 AN: 290

European-Non Finnish (NFE) AF: 0.672 AC: 45547 AN: 67798

Other (OTH) AF: 0.561 AC: 1166 AN: 2080

Alfa AF: 0.612 Hom.: 13194

Bravo AF: 0.505

Asia WGS AF: 0.476 AC: 1659 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.018
DANN	Benign	0.33
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs1793953; hg19: chr12-48393526; COSMIC: COSV61531117; COSMIC: COSV61531117;