rs766440021

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6

The NM_080680.3(COL11A2):c.2065C>T(p.Pro689Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.61

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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.

BP6

Variant 6-33176997-G-A is Benign according to our data. Variant chr6-33176997-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505322.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.2065C>T	p.Pro689Ser	missense_variant	25/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL11A2	ENST00000341947.7 linkuse as main transcript	c.2065C>T	p.Pro689Ser	missense_variant	25/66	5	NM_080680.3	ENSP00000339915	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.1807C>T	p.Pro603Ser	missense_variant	23/64	5		ENSP00000363840	A1
COL11A2	ENST00000361917.6 linkuse as main transcript	c.640C>T	p.Pro214Ser	missense_variant	12/24	5		ENSP00000355123
COL11A2	ENST00000477772.1 linkuse as main transcript	n.272+12C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

241170

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131454

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459072

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725676

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2016

The p.Pro689Ser variant in COL11A2 has not been previously reported in individua ls with hearing loss. This variant has been identified in 1/50332 European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs766440021); however, this frequency is not high enough to rule out a p athogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro689Ser variant is uncertain. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.088

T;T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.76

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

0.67

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.7

D;D;D

REVEL

Uncertain

0.63

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.074

T;T;T

Vest4

0.48

MutPred

0.41

.;Gain of phosphorylation at P689 (P = 0.0051);.;

MVP

0.88

MPC

0.40

ClinPred

0.85

GERP RS

3.4

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over