rs142962835

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_080680.3(COL11A2):ā€‹c.3860A>Gā€‹(p.Asp1287Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000951 in 1,596,552 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0046 ( 2 hom., cov: 31)
Exomes š‘“: 0.00056 ( 14 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

4
8
4

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.86
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL11A2. . Gene score misZ 2.3685 (greater than the threshold 3.09). Trascript score misZ 3.3886 (greater than threshold 3.09). GenCC has associacion of gene with otospondylomegaepiphyseal dysplasia, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss, autosomal recessive nonsyndromic hearing loss 53, otospondylomegaepiphyseal dysplasia, autosomal dominant, nonsyndromic genetic hearing loss, fibrochondrogenesis, hearing loss, autosomal recessive, otospondylomegaepiphyseal dysplasia, autosomal recessive.
BP4
Computational evidence support a benign effect (MetaRNN=0.024410933).
BP6
Variant 6-33168752-T-C is Benign according to our data. Variant chr6-33168752-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00464 (705/151862) while in subpopulation AFR AF= 0.0158 (655/41364). AF 95% confidence interval is 0.0148. There are 2 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL11A2NM_080680.3 linkuse as main transcriptc.3860A>G p.Asp1287Gly missense_variant 53/66 ENST00000341947.7 NP_542411.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL11A2ENST00000341947.7 linkuse as main transcriptc.3860A>G p.Asp1287Gly missense_variant 53/665 NM_080680.3 ENSP00000339915 P4
COL11A2ENST00000374708.8 linkuse as main transcriptc.3602A>G p.Asp1201Gly missense_variant 51/645 ENSP00000363840 A1
COL11A2ENST00000477772.1 linkuse as main transcriptn.273-2936A>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00466
AC:
707
AN:
151744
Hom.:
2
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00184
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00336
GnomAD3 exomes
AF:
0.00111
AC:
244
AN:
219958
Hom.:
0
AF XY:
0.000733
AC XY:
87
AN XY:
118636
show subpopulations
Gnomad AFR exome
AF:
0.0157
Gnomad AMR exome
AF:
0.000627
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.000724
GnomAD4 exome
AF:
0.000563
AC:
813
AN:
1444690
Hom.:
14
Cov.:
35
AF XY:
0.000470
AC XY:
337
AN XY:
717300
show subpopulations
Gnomad4 AFR exome
AF:
0.0173
Gnomad4 AMR exome
AF:
0.000725
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000191
Gnomad4 NFE exome
AF:
0.000124
Gnomad4 OTH exome
AF:
0.00121
GnomAD4 genome
AF:
0.00464
AC:
705
AN:
151862
Hom.:
2
Cov.:
31
AF XY:
0.00445
AC XY:
330
AN XY:
74208
show subpopulations
Gnomad4 AFR
AF:
0.0158
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00102
Hom.:
1
Bravo
AF:
0.00557
ESP6500AA
AF:
0.0125
AC:
55
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00123
AC:
149
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMay 02, 2018This 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. -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Asp1287Gly in Exon 53 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 1.2% (45/3724) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs142962835). -
Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.087
T;T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
MetaRNN
Benign
0.024
T;T;T
MetaSVM
Uncertain
0.66
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-5.9
D;D;D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.048
D;D;T
Vest4
0.69
MVP
0.84
MPC
0.44
ClinPred
0.039
T
GERP RS
3.8
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142962835; hg19: chr6-33136529; API