6-33167508-G-T

Position:

• chr6-33167508-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_080680.3(COL11A2):​c.4040C>A​(p.Pro1347Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,612,728 control chromosomes in the GnomAD database, including 3 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 0.00081 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.51

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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=0.024949074).
• BP6: Variant 6-33167508-G-T is Benign according to our data. Variant chr6-33167508-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162981.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000808 (123/152224) while in subpopulation AFR AF= 0.00284 (118/41530). AF 95% confidence interval is 0.00242. There are 2 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.4040C>A	p.Pro1347Gln	missense_variant	56/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.4040C>A	p.Pro1347Gln	missense_variant	56/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.3782C>A	p.Pro1261Gln	missense_variant	54/64	5		ENSP00000363840.4
COL11A2	ENST00000683572.1	n.7C>A		non_coding_transcript_exon_variant	1/9
COL11A2	ENST00000477772.1	n.273-1692C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000261 AC: 63 AN: 241766 Hom.: 1 AF XY: 0.000151 AC XY: 20 AN XY: 132250

Gnomad AFR exome AF: 0.00340

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000883 AC: 129 AN: 1460504 Hom.: 1 Cov.: 40 AF XY: 0.0000606 AC XY: 44 AN XY: 726552

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74442

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.000262

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: 0.000473

Alfa AF: 0.0000726 Hom.: 0

Bravo AF: 0.000963

ESP6500AA AF: 0.00132 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000306 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2018	The p.Pro1347Gln variant in COL11A2 is classified as likely benign because it ha s been identified in 0.3% (74/22572) of African chromosomes including 2 homozygo tes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ). ACMG/AMP Criteria applied: BS1. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant;C1864746:Autosomal recessive nonsyndromic hearing loss 53;C1866095:Autosomal dominant nonsyndromic hearing loss 13;C3281128:Fibrochondrogenesis 2;C5551484:Otospondylomegaepiphyseal dysplasia, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.084	T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Uncertain	0.75	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.11	T;T;T
Vest4		0.46
MVP		0.72
MPC		0.31
ClinPred		0.12	T
GERP RS		4.1
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142890313; hg19: chr6-33135285;