6-33163694-A-G

Position:

• chr6-33163694-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_080680.3(COL11A2):​c.5195T>C​(p.Val1732Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.5195T>C	p.Val1732Ala	missense_variant	66/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.5195T>C	p.Val1732Ala	missense_variant	66/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.4937T>C	p.Val1646Ala	missense_variant	64/64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.985T>C		non_coding_transcript_exon_variant	9/9	2
COL11A2	ENST00000683572.1	n.1001T>C		non_coding_transcript_exon_variant	9/9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 13, 2023

Variant summary: COL11A2 c.5195T>C (p.Val1732Ala) results in a non-conservative amino acid change located in the Fibrillar collagen, C-terminal (IPR000885) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5195T>C in individuals affected with COL11A2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.089	T;T;T
Vest4		0.44
MutPred		0.75		.;Gain of disorder (P = 0.0332);.;
MVP		0.89
MPC		0.41
ClinPred		0.96	D
GERP RS		4.9
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33131471;