chr6-33185751-C-T

Variant names:

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.826G>A(p.Glu276Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,340,386 control chromosomes in the GnomAD database, including 67,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E276R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.33 ( 7530 hom., cov: 24)

Exomes 𝑓: 0.31 ( 59702 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.22

Publications

36 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:

ENSG00000305994 (HGNC:):

ENSG00000305994 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=0.0024698675).

BP6

Variant 6-33185751-C-T is Benign according to our data. Variant chr6-33185751-C-T is described in ClinVar as Benign. ClinVar VariationId is 46569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 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
COL11A2	NM_080680.3	MANE Select	c.826G>A	p.Glu276Lys	missense	Exon 6 of 66	NP_542411.2
COL11A2	NM_001424108.1		c.826G>A	p.Glu276Lys	missense	Exon 6 of 65	NP_001411037.1
COL11A2	NM_001424109.1		c.-21G>A		5_prime_UTR	Exon 6 of 66	NP_001411038.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.826G>A	p.Glu276Lys	missense	Exon 6 of 66	ENSP00000339915.2
COL11A2	ENST00000930122.1		c.826G>A	p.Glu276Lys	missense	Exon 6 of 65	ENSP00000600181.1
COL11A2	ENST00000374708.8	TSL:5	c.799-697G>A		intron	N/A	ENSP00000363840.4

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

46741

AN:

141668

Hom.:

7527

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.382

Gnomad EAS

AF:

0.236

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.343

GnomAD2 exomes

AF:

0.297

AC:

73141

AN:

246010

AF XY:

0.306

show subpopulations

Gnomad AFR exome

AF:

0.367

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.372

Gnomad EAS exome

AF:

0.238

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.313

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.311

AC:

372581

AN:

1198634

Hom.:

59702

Cov.:

AF XY:

0.315

AC XY:

187391

AN XY:

594858

show subpopulations

African (AFR)

AF:

0.390

AC:

10108

AN:

25908

American (AMR)

AF:

0.197

AC:

7346

AN:

37222

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

6255

AN:

16744

East Asian (EAS)

AF:

0.242

AC:

4039

AN:

16670

South Asian (SAS)

AF:

0.387

AC:

32020

AN:

82774

European-Finnish (FIN)

AF:

0.220

AC:

6895

AN:

31318

Middle Eastern (MID)

AF:

0.374

AC:

1622

AN:

4342

European-Non Finnish (NFE)

AF:

0.309

AC:

290701

AN:

940194

Other (OTH)

AF:

0.313

AC:

13595

AN:

43462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

10338

20676

31014

41352

51690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10890

21780

32670

43560

54450

<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:

0.330

AC:

46758

AN:

141752

Hom.:

7530

Cov.:

AF XY:

0.329

AC XY:

22398

AN XY:

68050

show subpopulations

African (AFR)

AF:

0.380

AC:

14397

AN:

37850

American (AMR)

AF:

0.298

AC:

4003

AN:

13454

Ashkenazi Jewish (ASJ)

AF:

0.382

AC:

1306

AN:

3416

East Asian (EAS)

AF:

0.235

AC:

1116

AN:

4754

South Asian (SAS)

AF:

0.387

AC:

1769

AN:

4568

European-Finnish (FIN)

AF:

0.245

AC:

2070

AN:

8452

Middle Eastern (MID)

AF:

0.391

AC:

108

AN:

276

European-Non Finnish (NFE)

AF:

0.317

AC:

20971

AN:

66146

Other (OTH)

AF:

0.341

AC:

665

AN:

1950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1519

3037

4556

6074

7593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.313

Hom.:

17260

Bravo

AF:

0.318

TwinsUK

AF:

0.315

AC:

1168

ALSPAC

AF:

0.308

AC:

1186

ESP6500AA

AF:

0.367

AC:

1108

ESP6500EA

AF:

0.314

AC:

1703

ExAC

AF:

0.302

AC:

35411

Asia WGS

AF:

0.328

AC:

1141

AN:

3478

EpiCase

AF:

0.315

EpiControl

AF:

0.330

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Fibrochondrogenesis 2 (2)

Otospondylomegaepiphyseal dysplasia, autosomal dominant (2)

Otospondylomegaepiphyseal dysplasia, autosomal recessive (2)

Autosomal dominant nonsyndromic hearing loss 13 (1)

Autosomal recessive nonsyndromic hearing loss 53 (1)

not provided (1)

Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

0.058

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.91

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.52

PhyloP100

1.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.85

REVEL

Uncertain

0.31

Sift

Benign

0.66

Sift4G

Benign

0.75

Vest4

0.17

ClinPred

0.019

GERP RS

3.8

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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