chr6-33188451-G-A

Position:

• chr6-33188451-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_080680.3(COL11A2):​c.517C>T​(p.Arg173Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R173Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.40

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 -4 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=0.022455275).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000499 (76/152218) while in subpopulation AMR AF= 0.00137 (21/15296). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.517C>T	p.Arg173Trp	missense_variant	4/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.517C>T	p.Arg173Trp	missense_variant	4/66	5	NM_080680.3	P4
COL11A2	ENST00000395194.1	c.517C>T	p.Arg173Trp	missense_variant	4/5	1
COL11A2	ENST00000374708.8	c.517C>T	p.Arg173Trp	missense_variant	4/64	5		A1
COL11A2	ENST00000682718.1	n.334C>T		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000158 AC: 39 AN: 246566 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 134408

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460764 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 726692

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74430

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000706

ESP6500AA AF: 0.000662 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000195 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2015

The p.Arg173Trp variant in COL11A2 has not been previously reported in individua ls with hearing loss, but has been identified in 0.14% (13/9144) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs146522169). Although this variant has been seen in the general popula tion, its frequency is not high enough to rule out a pathogenic role. Computatio nal prediction tools and conservation analysis suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. In summary, the clinical significance of the p.Arg173Trp variant i s uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;.;D;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M
MutationTaster	Benign	0.97	D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.097	T;D;T;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Vest4		0.57
MVP		0.46
MPC		1.1
ClinPred		0.076	T
GERP RS		2.8
gMVP		0.56

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

Other links and lift over

dbSNP: rs146522169; hg19: chr6-33156228;