rs373983482

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS1

The NM_080680.3(COL11A2):c.1427C>T(p.Ala476Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,611,866 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).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 1 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL11A2. . Gene score misZ 2.3685 (greater than the threshold 3.09). Trascript score misZ 3.3886 (greater than threshold 3.09). GenCC has associacion of gene with otospondylomegaepiphyseal dysplasia, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss, autosomal recessive nonsyndromic hearing loss 53, otospondylomegaepiphyseal dysplasia, autosomal dominant, nonsyndromic genetic hearing loss, fibrochondrogenesis, hearing loss, autosomal recessive, otospondylomegaepiphyseal dysplasia, autosomal recessive.

BP4

Computational evidence support a benign effect (MetaRNN=0.37145156).

BP6

Variant 6-33179738-G-A is Benign according to our data. Variant chr6-33179738-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000582 (85/1459800) while in subpopulation SAS AF= 0.000823 (71/86258). AF 95% confidence interval is 0.000668. There are 1 homozygotes in gnomad4_exome. There are 54 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.1427C>T	p.Ala476Val	missense_variant	13/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL11A2	ENST00000341947.7 linkuse as main transcript	c.1427C>T	p.Ala476Val	missense_variant	13/66	5	NM_080680.3	ENSP00000339915	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.1169C>T	p.Ala390Val	missense_variant	11/64	5		ENSP00000363840	A1
COL11A2	ENST00000361917.6 linkuse as main transcript	c.56C>T	p.Ala19Val	missense_variant	1/24	5		ENSP00000355123

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152066

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:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

249240

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1459800

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726376

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2013

The Ala476Val variant in COL11A2 has not been reported in individuals with heari ng loss or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong evidence for or against an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.096

T;T;.;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Uncertain

0.78

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Benign

0.086

T;T;T;D

Vest4

0.42

MutPred

0.40

.;Gain of MoRF binding (P = 0.0951);.;Gain of MoRF binding (P = 0.0951);

MVP

0.90

MPC

0.83

ClinPred

0.54

GERP RS

4.5

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over