rs1799911

Positions:

• chr6-33170900-G-A
• chr6-33170900-G-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.3384C>T​(p.Pro1128=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,612,232 control chromosomes in the GnomAD database, including 59,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4493 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55094 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -3.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-33170900-G-A is Benign according to our data. Variant chr6-33170900-G-A is described in ClinVar as [Benign]. Clinvar id is 226535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33170900-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.3384C>T	p.Pro1128=	synonymous_variant	46/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.3384C>T	p.Pro1128=	synonymous_variant	46/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.3126C>T	p.Pro1042=	synonymous_variant	44/64	5		A1
COL11A2	ENST00000477772.1	n.273-5084C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35230 AN: 151772 Hom.: 4490 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.260 AC: 64205 AN: 246510 Hom.: 9309 AF XY: 0.274 AC XY: 36816 AN XY: 134378

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.390

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.269 AC: 392957 AN: 1460342 Hom.: 55094 Cov.: 51 AF XY: 0.274 AC XY: 199311 AN XY: 726502

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.232 AC: 35232 AN: 151890 Hom.: 4493 Cov.: 32 AF XY: 0.231 AC XY: 17129 AN XY: 74214

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.255

Alfa AF: 0.276 Hom.: 5483

Bravo AF: 0.229

Asia WGS AF: 0.319 AC: 1109 AN: 3478

EpiCase AF: 0.285

EpiControl AF: 0.298

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro1128Pro in Exon 46 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 28.1% (1259/4488) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1799911). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -
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. -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:2

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

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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. -

Fibrochondrogenesis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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. -

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	-0.82
CADD	Benign	3.8
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1799911; hg19: chr6-33138677; COSMIC: COSV59496570;