chr6-33171551-C-T

Position:

• chr6-33171551-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_080680.3(COL11A2):​c.3174G>A​(p.Pro1058Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,613,278 control chromosomes in the GnomAD database, including 177,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19822 hom., cov: 32)
  • Exomes 𝑓: 0.46 (158000 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -4.29

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]

COL11A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 6-33171551-C-T is Benign according to our data. Variant chr6-33171551-C-T is described in ClinVar as [Benign]. Clinvar id is 46565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33171551-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.3174G>A	p.Pro1058Pro	synonymous_variant	43/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.3174G>A	p.Pro1058Pro	synonymous_variant	43/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2916G>A	p.Pro972Pro	synonymous_variant	41/64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.272+5458G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75873 AN: 151884 Hom.: 19786 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.486

GnomAD3 exomes AF: 0.449 AC: 112395 AN: 250226 Hom.: 26729 AF XY: 0.459 AC XY: 62115 AN XY: 135370

Gnomad AFR exome AF: 0.656

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.498

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.588

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.460 AC: 672638 AN: 1461276 Hom.: 158000 Cov.: 58 AF XY: 0.464 AC XY: 337381 AN XY: 726946

Gnomad4 AFR exome AF: 0.669

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.500 AC: 75951 AN: 152002 Hom.: 19822 Cov.: 32 AF XY: 0.495 AC XY: 36771 AN XY: 74290

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.484

Alfa AF: 0.466 Hom.: 25063

Bravo AF: 0.500

Asia WGS AF: 0.475 AC: 1652 AN: 3478

EpiCase AF: 0.454

EpiControl AF: 0.463

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro1058Pro in Exon 43 of COL11A2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 45.2% (3170/7020) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1799910). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Fibrochondrogenesis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autosomal dominant nonsyndromic hearing loss 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Stickler Syndrome, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.31
DANN	Benign	0.49

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: rs1799910; hg19: chr6-33139328; COSMIC: COSV59500329;