Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080680.3(COL11A2):c.4799G>A(p.Arg1600Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,581,402 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00085 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 41 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.89

Publications

11 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

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=0.01012671).

BP6

Variant 6-33164916-C-T is Benign according to our data. Variant chr6-33164916-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000854 (130/152186) while in subpopulation EAS AF = 0.0193 (100/5174). AF 95% confidence interval is 0.0163. There are 3 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

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
COL11A2	NM_080680.3	MANE Select	c.4799G>A	p.Arg1600Gln	missense	Exon 64 of 66	NP_542411.2
COL11A2	NM_001424108.1		c.4619G>A	p.Arg1540Gln	missense	Exon 63 of 65	NP_001411037.1
COL11A2	NM_080681.3		c.4541G>A	p.Arg1514Gln	missense	Exon 62 of 64	NP_542412.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.4799G>A	p.Arg1600Gln	missense	Exon 64 of 66	ENSP00000339915.2
COL11A2	ENST00000374708.8	TSL:5	c.4541G>A	p.Arg1514Gln	missense	Exon 62 of 64	ENSP00000363840.4
COL11A2	ENST00000477772.1	TSL:2	n.589G>A		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes

AF:

0.000868

AC:

132

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0197

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00216

AC:

435

AN:

201804

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000218

Gnomad EAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.000964

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00124

AC:

1768

AN:

1429216

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

912

AN XY:

707742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32936

American (AMR)

AF:

0.00

AC:

AN:

40386

Ashkenazi Jewish (ASJ)

AF:

0.000235

AC:

AN:

25544

East Asian (EAS)

AF:

0.0354

AC:

1362

AN:

38480

South Asian (SAS)

AF:

0.00283

AC:

231

AN:

81684

European-Finnish (FIN)

AF:

0.000923

AC:

AN:

50910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000493

AC:

AN:

1094382

Other (OTH)

AF:

0.00115

AC:

AN:

59166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000854

AC:

130

AN:

152186

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5174

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67978

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000914

Hom.:

Bravo

AF:

0.000884

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00201

AC:

242

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Connective tissue disorder (1)

Fibrochondrogenesis 2 (1)

not provided (1)

Otospondylomegaepiphyseal dysplasia, autosomal dominant (1)

Otospondylomegaepiphyseal dysplasia, autosomal dominant;C1864746:Autosomal recessive nonsyndromic hearing loss 53;C1866095:Autosomal dominant nonsyndromic hearing loss 13;C3281128:Fibrochondrogenesis 2;C5551484:Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)

Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)

Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.029

Eigen

Benign

-0.061

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.47

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

PhyloP100

3.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.038

Sift4G

Uncertain

0.049

Vest4

0.36

MVP

0.68

MPC

0.39

ClinPred

0.034

GERP RS

2.9

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(source)

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over