6-33164929-G-C

Variant names:

• chr6-33164929-G-C
• rs778962979
• NM_080680.3:c.4786C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080680.3(COL11A2):​c.4786C>G​(p.Arg1596Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.4786C>G	p.Arg1596Gly	missense_variant	Exon 64 of 66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.4786C>G	p.Arg1596Gly	missense_variant	Exon 64 of 66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.4528C>G	p.Arg1510Gly	missense_variant	Exon 62 of 64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.576C>G		non_coding_transcript_exon_variant	Exon 7 of 9	2
COL11A2	ENST00000683572.1	n.592C>G		non_coding_transcript_exon_variant	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000500 AC: 1 AN: 199846 Hom.: 0 AF XY: 0.00000938 AC XY: 1 AN XY: 106590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428412 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.58	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.83	T;T;T
Sift4G	Benign	0.46	T;T;T
Vest4		0.76
MutPred		0.75		.;Gain of catalytic residue at G1593 (P = 0.0495);.;
MVP		0.86
MPC		0.43
ClinPred		0.86	D
GERP RS		3.8
gMVP		0.63

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: rs778962979; hg19: chr6-33132706;