chr6-33170061-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_080680.3(COL11A2):​c.3622C>G​(p.Pro1208Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1208S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

4
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.610

Publications

1 publications found
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]
COL11A2 Gene-Disease associations (from GenCC):
  • autosomal dominant nonsyndromic hearing loss 13
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
  • nonsyndromic genetic hearing loss
    Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
  • otospondylomegaepiphyseal dysplasia, autosomal dominant
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
  • autosomal recessive nonsyndromic hearing loss 53
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • otospondylomegaepiphyseal dysplasia
    Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • otospondylomegaepiphyseal dysplasia, autosomal recessive
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • fibrochondrogenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.054613054).
BP6
Variant 6-33170061-G-C is Benign according to our data. Variant chr6-33170061-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1518020.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000138 (21/152244) while in subpopulation AFR AF = 0.000458 (19/41516). AF 95% confidence interval is 0.000299. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL11A2NM_080680.3 linkc.3622C>G p.Pro1208Ala missense_variant Exon 49 of 66 ENST00000341947.7 NP_542411.2 P13942A0A0C4DFS1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL11A2ENST00000341947.7 linkc.3622C>G p.Pro1208Ala missense_variant Exon 49 of 66 5 NM_080680.3 ENSP00000339915.2 A0A0C4DFS1
COL11A2ENST00000374708.8 linkc.3364C>G p.Pro1122Ala missense_variant Exon 47 of 64 5 ENSP00000363840.4 Q4VXY6
COL11A2ENST00000477772.1 linkn.273-4245C>G intron_variant Intron 5 of 8 2

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000459
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000526
AC:
13
AN:
247216
AF XY:
0.0000372
show subpopulations
Gnomad AFR exome
AF:
0.000328
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000901
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1460790
Hom.:
0
Cov.:
34
AF XY:
0.0000138
AC XY:
10
AN XY:
726710
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33480
American (AMR)
AF:
0.000157
AC:
7
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.0000191
AC:
1
AN:
52352
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111996
Other (OTH)
AF:
0.000116
AC:
7
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.000458
AC:
19
AN:
41516
American (AMR)
AF:
0.0000654
AC:
1
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.000121
ExAC
AF:
0.0000501
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
May 14, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jul 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
18
DANN
Benign
0.89
DEOGEN2
Benign
0.010
T;T;.
Eigen
Benign
-0.096
Eigen_PC
Benign
-0.035
FATHMM_MKL
Benign
0.15
N
M_CAP
Uncertain
0.088
D
MetaRNN
Benign
0.055
T;T;T
MetaSVM
Uncertain
0.44
D
PhyloP100
0.61
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.10
N;N;N
REVEL
Uncertain
0.48
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.59
T;T;T
Vest4
0.19
MutPred
0.45
.;Loss of catalytic residue at P1208 (P = 0.0231);.;
MVP
0.70
MPC
0.33
ClinPred
0.059
T
GERP RS
4.5
gMVP
0.20
Mutation Taster
=58/42
polymorphism

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

Other links and lift over

dbSNP: rs374515005; hg19: chr6-33137838; API