6-33186589-G-T

Position:

chr6-33186589-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000395194.1(COL11A2):c.836C>A(p.Pro279His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000483 in 1,614,138 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00050 ( 6 hom. )

Consequence

COL11A2
ENST00000395194.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.423

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033665001).

BP6

Variant 6-33186589-G-T is Benign according to our data. Variant chr6-33186589-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 162995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33186589-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000289 (44/152298) while in subpopulation SAS AF= 0.00435 (21/4824). AF 95% confidence interval is 0.00292. There are 1 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.798+38C>A		intron_variant		ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000395194.1 linkuse as main transcript	c.836C>A	p.Pro279His	missense_variant	5/5	1			P13942-9
COL11A2	ENST00000341947.7 linkuse as main transcript	c.798+38C>A		intron_variant		5	NM_080680.3	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.798+38C>A		intron_variant		5		A1
COL11A2	ENST00000682718.1 linkuse as main transcript	n.615+38C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000688

AC:

173

AN:

251342

Hom.:

AF XY:

0.000891

AC XY:

121

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00389

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000503

AC:

735

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000630

AC XY:

458

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00393

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000266

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.000289

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000339

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000914

AC:

111

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	COL11A2: BP4 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2015

p.Pro279His in exon 5 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 0.47% (78/16506) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs20098046). -

COL11A2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.94

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.029

M_CAP

Benign

0.0021

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PROVEAN

Benign

-1.1

REVEL

Benign

0.024

Sift

Pathogenic

0.0

Sift4G

Benign

0.066

Vest4

0.10

MVP

0.068

ClinPred

0.010

GERP RS

-2.4

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

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