rs766440021

chr6-33176997-G-Achr6-33176997-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP6

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). Synonymous variant affecting the same amino acid position (i.e. P689P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL11A2
• 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	UniProt
COL11A2	NM_080680.3	c.2065C>T	p.Pro689Ser	missense_variant	25/66	ENST00000341947.7

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000124 AC: 3 AN: 241170 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131454

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: 10 AN: 1459072 Hom.: 0 Cov.: 34 AF XY: 0.00000827 AC XY: 6 AN XY: 725676

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.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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

Invitae

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.088	T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
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	D
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

Other links and lift over

dbSNP: rs766440021; hg19: chr6-33144774;