rs534570825

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_080680.3(COL11A2):c.3725C>T(p.Ser1242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,612,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1242S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000086 ( 1 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 9.28

Publications

3 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33568656).

BP6

Variant 6-33169456-G-A is Benign according to our data. Variant chr6-33169456-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 356389.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000171 (26/152214) while in subpopulation SAS AF = 0.00104 (5/4820). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.3725C>T	p.Ser1242Leu	missense	Exon 51 of 66	NP_542411.2
COL11A2	NM_001424108.1		c.3545C>T	p.Ser1182Leu	missense	Exon 50 of 65	NP_001411037.1
COL11A2	NM_080681.3		c.3467C>T	p.Ser1156Leu	missense	Exon 49 of 64	NP_542412.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.3725C>T	p.Ser1242Leu	missense	Exon 51 of 66	ENSP00000339915.2
COL11A2	ENST00000930122.1		c.3545C>T	p.Ser1182Leu	missense	Exon 50 of 65	ENSP00000600181.1
COL11A2	ENST00000374708.8	TSL:5	c.3467C>T	p.Ser1156Leu	missense	Exon 49 of 64	ENSP00000363840.4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000134

AC:

AN:

246426

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.000265

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000438

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000856

AC:

125

AN:

1460668

Hom.:

Cov.:

AF XY:

0.0000895

AC XY:

AN XY:

726662

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000353

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52214

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1112004

Other (OTH)

AF:

0.0000662

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000171

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41524

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000160

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.000143

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Fibrochondrogenesis 2 (1)

Inborn genetic diseases (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

0.085

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

Eigen

Benign

-0.018

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.34

MetaSVM

Uncertain

0.30

PhyloP100

9.3

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.47

Sift

Benign

0.089

Sift4G

Benign

0.19

Vest4

0.24

MVP

0.75

MPC

0.30

ClinPred

0.072

GERP RS

4.7

gMVP

0.26

Mutation Taster

=69/31

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

Computational scores

Splicing

Publications

Other links and lift over