rs1635560

Variant names:

• chr12-47974046-G-A
• rs1635560
• NM_001844.5:c.4317+43C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47974046-G-A
• chr12-47974046-G-C
• chr12-47974046-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.4317+43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,520 control chromosomes in the GnomAD database, including 44,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3795 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40409 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.37
• Publications: 10 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=-0.9).
• BP6: Variant 12-47974046-G-A is Benign according to our data. Variant chr12-47974046-G-A is described in ClinVar as [Benign]. Clinvar id is 258240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.4317+43C>T		intron_variant	Intron 53 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.4317+43C>T		intron_variant	Intron 53 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.4110+43C>T		intron_variant	Intron 52 of 52	1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.3403+43C>T		intron_variant	Intron 36 of 36	2

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33630 AN: 151992 Hom.: 3790 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.221 AC: 55094 AN: 249444 AF XY: 0.229

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.233 AC: 340967 AN: 1461410 Hom.: 40409 Cov.: 35 AF XY: 0.237 AC XY: 172112 AN XY: 726998

African (AFR) AF: 0.212 AC: 7105 AN: 33478

American (AMR) AF: 0.146 AC: 6551 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5110 AN: 26136

East Asian (EAS) AF: 0.219 AC: 8699 AN: 39696

South Asian (SAS) AF: 0.297 AC: 25574 AN: 86162

European-Finnish (FIN) AF: 0.198 AC: 10575 AN: 53284

Middle Eastern (MID) AF: 0.272 AC: 1568 AN: 5760

European-Non Finnish (NFE) AF: 0.236 AC: 261990 AN: 1111802

Other (OTH) AF: 0.229 AC: 13795 AN: 60370

GnomAD4 genome AF: 0.221 AC: 33669 AN: 152110 Hom.: 3795 Cov.: 32 AF XY: 0.218 AC XY: 16224 AN XY: 74384

African (AFR) AF: 0.208 AC: 8640 AN: 41496

American (AMR) AF: 0.181 AC: 2766 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3468

East Asian (EAS) AF: 0.209 AC: 1080 AN: 5164

South Asian (SAS) AF: 0.300 AC: 1447 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2018 AN: 10586

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16288 AN: 67972

Other (OTH) AF: 0.226 AC: 479 AN: 2116

Alfa AF: 0.234 Hom.: 11056

Bravo AF: 0.218

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.50
PhyloP100		-2.4
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: rs1635560; hg19: chr12-48367829; COSMIC: COSV61531043; COSMIC: COSV61531043;