rs2855453

chr6-33166615-C-Achr6-33166615-C-Gchr6-33166615-C-T

Variant summary

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

The NM_080680.3(COL11A2):c.4339-49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 1,611,724 control chromosomes in the GnomAD database, including 386,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35422 hom., cov: 29)
  • Exomes 𝑓: 0.69 (350673 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.753

Genes affected

COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-33166615-C-A is Benign according to our data. Variant chr6-33166615-C-A is described in ClinVar as [Benign]. Clinvar id is 674799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.4339-49G>T		intron_variant		ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.4339-49G>T		intron_variant		5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.4081-49G>T		intron_variant		5		A1
COL11A2	ENST00000477772.1	n.273-799G>T		intron_variant, non_coding_transcript_variant		2
COL11A2	ENST00000683572.1	n.234+176G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.679 AC: 102845 AN: 151548 Hom.: 35392 Cov.: 29

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.812

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.713

GnomAD3 exomes AF: 0.732 AC: 180080 AN: 246104 Hom.: 66992 AF XY: 0.736 AC XY: 98157 AN XY: 133332

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.834

Gnomad EAS exome AF: 0.970

Gnomad SAS exome AF: 0.827

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.689 AC: 1005966 AN: 1460058 Hom.: 350673 Cov.: 40 AF XY: 0.694 AC XY: 504122 AN XY: 726344

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.780

Gnomad4 ASJ exome AF: 0.833

Gnomad4 EAS exome AF: 0.980

Gnomad4 SAS exome AF: 0.825

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.712

GnomAD4 genome AF: 0.679 AC: 102931 AN: 151666 Hom.: 35422 Cov.: 29 AF XY: 0.684 AC XY: 50668 AN XY: 74116

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.824

Gnomad4 EAS AF: 0.964

Gnomad4 SAS AF: 0.841

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.669

Gnomad4 OTH AF: 0.716

Alfa AF: 0.693 Hom.: 32459

Bravo AF: 0.684

Asia WGS AF: 0.859 AC: 2987 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Autosomal recessive nonsyndromic hearing loss 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 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. -

Autosomal dominant nonsyndromic hearing loss 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Fibrochondrogenesis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.7
Dann	Benign	0.74

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: rs2855453; hg19: chr6-33134392; COSMIC: COSV59503025;