rs374515005

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BP6

The NM_080680.3(COL11A2):​c.3622C>T​(p.Pro1208Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,612,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.610
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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=0.30328745).
BP6
Variant 6-33170061-G-A is Benign according to our data. Variant chr6-33170061-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178324.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL11A2NM_080680.3 linkuse as main transcriptc.3622C>T p.Pro1208Ser missense_variant 49/66 ENST00000341947.7 NP_542411.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL11A2ENST00000341947.7 linkuse as main transcriptc.3622C>T p.Pro1208Ser missense_variant 49/665 NM_080680.3 ENSP00000339915 P4
COL11A2ENST00000374708.8 linkuse as main transcriptc.3364C>T p.Pro1122Ser missense_variant 47/645 ENSP00000363840 A1
COL11A2ENST00000477772.1 linkuse as main transcriptn.273-4245C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000809
AC:
20
AN:
247216
Hom.:
0
AF XY:
0.0000743
AC XY:
10
AN XY:
134574
show subpopulations
Gnomad AFR exome
AF:
0.000131
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.000108
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000507
AC:
74
AN:
1460790
Hom.:
0
Cov.:
34
AF XY:
0.0000482
AC XY:
35
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000191
Gnomad4 NFE exome
AF:
0.0000522
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.000331
AC:
1
ESP6500EA
AF:
0.000185
AC:
1
ExAC
AF:
0.0000417
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 31, 2022Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2023- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 29, 2014The Pro1208Ser variant in COL11A2 has not been previously reported in individual s with hearing loss, but has been identified in 0.02% (1/5418) of European Ameri can chromosomes and 0.03% (1/3022) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs374515005). Although this variant has been seen in the general population, its frequency i s not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the Pro1208Ser variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, the clinical significance of the Pro1208Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.025
T;T;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Benign
0.22
N
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.30
T;T;T
MetaSVM
Uncertain
0.72
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Uncertain
0.53
Sift
Benign
0.22
T;T;T
Sift4G
Benign
0.15
T;T;T
Vest4
0.25
MVP
0.72
MPC
0.34
ClinPred
0.42
T
GERP RS
4.5
gMVP
0.33

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: rs374515005; hg19: chr6-33137838; COSMIC: COSV59496096; API