rs141140798

chr6-33179783-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_080680.3(COL11A2):c.1382G>A(p.Gly461Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00039 in 1,611,726 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G461C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 5.87

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL11A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1086891).
• BP6: Variant 6-33179783-C-T is Benign according to our data. Variant chr6-33179783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284958.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00044 (67/152314) while in subpopulation AMR AF= 0.0015 (23/15308). AF 95% confidence interval is 0.00103. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.1382G>A	p.Gly461Asp	missense_variant	13/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.1382G>A	p.Gly461Asp	missense_variant	13/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.1124G>A	p.Gly375Asp	missense_variant	11/64	5		A1
COL11A2	ENST00000361917.6	c.11G>A	p.Gly4Asp	missense_variant	1/24	5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000526 AC: 131 AN: 249246 Hom.: 0 AF XY: 0.000600 AC XY: 81 AN XY: 135052

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000384 AC: 561 AN: 1459412 Hom.: 1 Cov.: 33 AF XY: 0.000413 AC XY: 300 AN XY: 726184

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000784

Gnomad4 NFE exome AF: 0.000419

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74470

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.000657

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000491

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	COL11A2: PP3, BS1:Supporting -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Gly461Asp var iant in COL11A2 has been previously reported by our laboratory in 2 families wit h hearing loss; however, it did not segregate with hearing loss in one of the fa milies. This variant has been identified in several populations including in 29/ 34412 Latino chromosomes and 87/126550 of European chromosomes by the Genome Ag gregation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs14114079 8). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tool s and conservation analyses do not provide strong support for or against an impa ct to the protein. In summary, while the clinical significance of the p.Gly461As p variant is uncertain, the population frequency and non-segregation data sugges t that it is more likely to be benign. ACMG/AMP criteria applied: BS4, BS1_Suppo rting. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PP3_Supporting -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;.;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	N;N;N;D
REVEL	Uncertain	0.52
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Vest4		0.72
MVP		0.79
MPC		1.2
ClinPred		0.092	T
GERP RS		4.5
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs141140798; hg19: chr6-33147560; COSMIC: COSV59504558; COSMIC: COSV59504558;