rs1635544

Positions:

• chr12-47986248-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.1527+88T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 934,790 control chromosomes in the GnomAD database, including 103,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17069 hom., cov: 32)
  • Exomes 𝑓: 0.47 (86312 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.747

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-47986248-A-G is Benign according to our data. Variant chr12-47986248-A-G is described in ClinVar as [Benign]. Clinvar id is 585507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1527+88T>C		intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1527+88T>C		intron_variant		1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.1320+88T>C		intron_variant		1		ENSP00000338213
COL2A1	ENST00000493991.5	n.451+88T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71511 AN: 151862 Hom.: 17061 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.469

GnomAD4 exome AF: 0.466 AC: 364687 AN: 782810 Hom.: 86312 AF XY: 0.468 AC XY: 191012 AN XY: 408306

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.292

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.550

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.473

Gnomad4 OTH exome AF: 0.475

GnomAD4 genome AF: 0.471 AC: 71540 AN: 151980 Hom.: 17069 Cov.: 32 AF XY: 0.467 AC XY: 34710 AN XY: 74264

Gnomad4 AFR AF: 0.509

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.569

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.472

Gnomad4 OTH AF: 0.464

Alfa AF: 0.463 Hom.: 33508

Bravo AF: 0.466

Asia WGS AF: 0.469 AC: 1629 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.83
DANN	Benign	0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs1635544; hg19: chr12-48380031; COSMIC: COSV61528174; COSMIC: COSV61528174;