6-33176030-C-T

Position:

• chr6-33176030-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_080680.3(COL11A2):​c.2254G>A​(p.Val752Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,612,886 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 2.35

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 Uncertain_significance. Variant got 0 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=0.2702949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.2254G>A	p.Val752Met	missense_variant	29/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.2254G>A	p.Val752Met	missense_variant	29/66	5	NM_080680.3	ENSP00000339915	P4
COL11A2	ENST00000374708.8	c.1996G>A	p.Val666Met	missense_variant	27/64	5		ENSP00000363840	A1
COL11A2	ENST00000361917.6	c.829G>A	p.Val277Met	missense_variant	16/24	5		ENSP00000355123
COL11A2	ENST00000477772.1	n.272+979G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000142 AC: 35 AN: 247050 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134560

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1460794 Hom.: 1 Cov.: 35 AF XY: 0.000341 AC XY: 248 AN XY: 726712

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000412

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74270

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.000369 AC: 2

ExAC AF: 0.000110 AC: 13

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2024	Observed in the homozygous state in an individual with clinical features of a mitochondrial disorder who also harbored a pathogenic variant in QRICH1 and was homoplasmic for two mitochondrial variants (PMID: 28692176); Observed in an individual with nonsyndromic hearing loss (NSHL) in published literature (PMID: 27068579); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.1996G>A, p.(V666M); This variant is associated with the following publications: (PMID: 28692176, 27068579) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	COL11A2: PM2 -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 25, 2022

Variant summary: COL11A2 c.2254G>A (p.Val752Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 247050 control chromosomes (gnomAD), predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. c.2254G>A has been reported in the literature in at least one individual affected with hearing loss (Sommen_2016). The variant was also found in the homozygous state in an individual with facial dysmorphology, intellectual disability/developmental delay, muscle weakness and pain, and poor growth; this individual also carried a de novo pathogenic variant in QRICH1 (c.1953dup, p.Arg652fs) which was concordant with their observed phenotype (Ververi_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

COL11A2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The COL11A2 c.2254G>A variant is predicted to result in the amino acid substitution p.Val752Met. This variant has been observed in a cohort of patients with non-syndromic hearing loss (reported as c.1996G>A, p.Val666Met in Table S1, Sommen et al. 2016. PubMed ID: 27068579). This variant was also reported in the homozygous state, along with a de novo pathogenic variant in QRICH1 gene, in a patient with idiopathic developmental delay (reported as NM_080681.2:c.1996G>A in Ververi et al. 2018. PubMed ID: 28692176). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fibrochondrogenesis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.13	T;T;T
Vest4		0.38
MVP		0.73
MPC		0.92
ClinPred		0.17	T
GERP RS		4.8
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs201076557; hg19: chr6-33143807; COSMIC: COSV59496221; COSMIC: COSV59496221;