rs41317883

chr12-47996652-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001844.5(COL2A1):c.532-27T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,601,660 control chromosomes in the GnomAD database, including 1,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (55 hom., cov: 33)
  • Exomes 𝑓: 0.034 (980 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.407

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=-0.84).
• BP6: Variant 12-47996652-A-T is Benign according to our data. Variant chr12-47996652-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 258241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0233 (3555/152308) while in subpopulation NFE AF= 0.0348 (2365/68034). AF 95% confidence interval is 0.0336. There are 55 homozygotes in gnomad4. There are 1712 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.532-27T>A		intron_variant		ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.532-27T>A		intron_variant		1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.325-27T>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3554 AN: 152190 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0243 AC: 6104 AN: 251146 Hom.: 116 AF XY: 0.0243 AC XY: 3292 AN XY: 135700

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0338 AC: 48962 AN: 1449352 Hom.: 980 Cov.: 28 AF XY: 0.0326 AC XY: 23521 AN XY: 721882

Gnomad4 AFR exome AF: 0.00539

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0267

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00576

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0312

GnomAD4 genome AF: 0.0233 AC: 3555 AN: 152308 Hom.: 55 Cov.: 33 AF XY: 0.0230 AC XY: 1712 AN XY: 74492

Gnomad4 AFR AF: 0.00659

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0281 Hom.: 13

Bravo AF: 0.0227

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.57
Dann	Benign	0.52

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: rs41317883; hg19: chr12-48390435;