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rs148262058

chr6-33166522-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_080680.3(COL11A2):c.4383C>T(p.Pro1461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,612,404 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00087 ( 2 hom. )

Consequence

COL11A2
NM_080680.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -1.93
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 -10 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-33166522-G-A is Benign according to our data. Variant chr6-33166522-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226537.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=2}. Variant chr6-33166522-G-A is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.93 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/152074) while in subpopulation NFE AF= 0.00137 (93/67920). AF 95% confidence interval is 0.00114. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL11A2NM_080680.3 linkuse as main transcriptc.4383C>T p.Pro1461= synonymous_variant 60/66 ENST00000341947.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL11A2ENST00000341947.7 linkuse as main transcriptc.4383C>T p.Pro1461= synonymous_variant 60/665 NM_080680.3 P4
COL11A2ENST00000374708.8 linkuse as main transcriptc.4125C>T p.Pro1375= synonymous_variant 58/645 A1
COL11A2ENST00000477772.1 linkuse as main transcriptn.273-706C>T intron_variant, non_coding_transcript_variant 2
COL11A2ENST00000683572.1 linkuse as main transcriptn.234+269C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00147
AC:
224
AN:
151956
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0115
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00137
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00165
AC:
412
AN:
249420
Hom.:
0
AF XY:
0.00161
AC XY:
217
AN XY:
134872
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.000604
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.0118
Gnomad NFE exome
AF:
0.00125
Gnomad OTH exome
AF:
0.00148
GnomAD4 exome
AF:
0.000874
AC:
1277
AN:
1460330
Hom.:
2
Cov.:
33
AF XY:
0.000885
AC XY:
643
AN XY:
726506
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.000346
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0114
Gnomad4 NFE exome
AF:
0.000539
Gnomad4 OTH exome
AF:
0.000779
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00147
AC:
224
AN:
152074
Hom.:
1
Cov.:
31
AF XY:
0.00200
AC XY:
149
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.0115
Gnomad4 NFE
AF:
0.00137
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00156
Hom.:
1
Bravo
AF:
0.000385
EpiCase
AF:
0.000709
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 04, 2021- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024COL11A2: BP4, BP7 -
Otospondylomegaepiphyseal dysplasia, autosomal recessive Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Fibrochondrogenesis 2 Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 02, 2015p.Pro1461Pro in Exon 60 of COL11A2: This variant is not expected to have clinica l significance because it does not alter an amino acid residue, is not located w ithin the splice consensus sequence, and has been identified in 1.4% (88/6428) o f Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs148262058). -
COL11A2-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 02, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Stickler Syndrome, Dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.62
Cadd
Benign
1.8
Dann
Benign
0.55

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

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

Other links and lift over

dbSNP: rs148262058; hg19: chr6-33134299; API