rs2855430

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_080680.3(COL11A2):c.2681C>T(p.Pro894Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,611,686 control chromosomes in the GnomAD database, including 14,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P894R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 1012 hom., cov: 27)

Exomes 𝑓: 0.13 ( 13931 hom. )

Consequence

COL11A2
NM_080680.3 missense, splice_region

Scores

Splicing: ADA: 0.9241

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.76

Publications

57 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, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
otospondylomegaepiphyseal dysplasia, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal recessive nonsyndromic hearing loss 53
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
otospondylomegaepiphyseal dysplasia
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
otospondylomegaepiphyseal dysplasia, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

COL11A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038810372).

BP6

Variant 6-33173503-G-A is Benign according to our data. Variant chr6-33173503-G-A is described in ClinVar as Benign. ClinVar VariationId is 46561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080680.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL11A2	NM_080680.3	MANE Select	c.2681C>T	p.Pro894Leu	missense splice_region	Exon 36 of 66	NP_542411.2	A0A0C4DFS1
COL11A2	NM_001424108.1		c.2501C>T	p.Pro834Leu	missense splice_region	Exon 35 of 65	NP_001411037.1
COL11A2	NM_080681.3		c.2423C>T	p.Pro808Leu	missense splice_region	Exon 34 of 64	NP_542412.2	Q4VXY6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.2681C>T	p.Pro894Leu	missense splice_region	Exon 36 of 66	ENSP00000339915.2	A0A0C4DFS1
COL11A2	ENST00000930122.1		c.2501C>T	p.Pro834Leu	missense splice_region	Exon 35 of 65	ENSP00000600181.1
COL11A2	ENST00000374708.8	TSL:5	c.2423C>T	p.Pro808Leu	missense splice_region	Exon 34 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15312

AN:

151370

Hom.:

1012

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0720

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.0819

GnomAD2 exomes

AF:

0.122

AC:

29605

AN:

243556

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.0594

Gnomad ASJ exome

AF:

0.0889

Gnomad EAS exome

AF:

0.0966

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.134

AC:

195391

AN:

1460200

Hom.:

13931

Cov.:

AF XY:

0.135

AC XY:

98184

AN XY:

726324

show subpopulations

African (AFR)

AF:

0.0239

AC:

800

AN:

33454

American (AMR)

AF:

0.0600

AC:

2680

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0907

AC:

2370

AN:

26120

East Asian (EAS)

AF:

0.112

AC:

4437

AN:

39676

South Asian (SAS)

AF:

0.184

AC:

15828

AN:

86224

European-Finnish (FIN)

AF:

0.178

AC:

9334

AN:

52426

Middle Eastern (MID)

AF:

0.106

AC:

609

AN:

5760

European-Non Finnish (NFE)

AF:

0.137

AC:

151869

AN:

1111504

Other (OTH)

AF:

0.124

AC:

7464

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

9742

19485

29227

38970

48712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5506

11012

16518

22024

27530

<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:

0.101

AC:

15309

AN:

151486

Hom.:

1012

Cov.:

AF XY:

0.103

AC XY:

7638

AN XY:

73992

show subpopulations

African (AFR)

AF:

0.0275

AC:

1135

AN:

41302

American (AMR)

AF:

0.0720

AC:

1096

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3470

East Asian (EAS)

AF:

0.108

AC:

551

AN:

5096

South Asian (SAS)

AF:

0.182

AC:

869

AN:

4762

European-Finnish (FIN)

AF:

0.179

AC:

1880

AN:

10516

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.137

AC:

9266

AN:

67814

Other (OTH)

AF:

0.0829

AC:

174

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

699

1398

2098

2797

3496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.121

Hom.:

4787

Bravo

AF:

0.0870

TwinsUK

AF:

0.140

AC:

518

ALSPAC

AF:

0.138

AC:

532

ESP6500AA

AF:

0.0273

AC:

120

ESP6500EA

AF:

0.131

AC:

1130

ExAC

AF:

0.122

AC:

14660

Asia WGS

AF:

0.117

AC:

405

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.120

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Fibrochondrogenesis 2 (1)

not provided (1)

Otospondylomegaepiphyseal dysplasia, autosomal dominant (1)

Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)

Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.81

PhyloP100

9.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.28

Sift

Benign

0.089

Sift4G

Uncertain

0.018

Vest4

0.36

MPC

0.99

ClinPred

0.029

GERP RS

4.0

gMVP

0.31

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.85

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over