chr6-33163724-G-A

Variant names:

• chr6-33163724-G-A
• rs2229792
• NM_080680.3:c.5165C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080680.3(COL11A2):​c.5165C>T​(p.Pro1722Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,613,068 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1722P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (69 hom., cov: 32)
  • Exomes 𝑓: 0.020 (466 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.801
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive nonsyndromic hearing loss 53

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019938052).
• BP6: Variant 6-33163724-G-A is Benign according to our data. Variant chr6-33163724-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0185 (2813/152296) while in subpopulation NFE AF = 0.0244 (1659/68010). AF 95% confidence interval is 0.0234. There are 69 homozygotes in GnomAd4. There are 1349 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080680.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	NM_080680.3	MANE Select	c.5165C>T	p.Pro1722Leu	missense	Exon 66 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.4985C>T	p.Pro1662Leu	missense	Exon 65 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.4907C>T	p.Pro1636Leu	missense	Exon 64 of 64	NP_542412.2	Q4VXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.5165C>T	p.Pro1722Leu	missense	Exon 66 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.4985C>T	p.Pro1662Leu	missense	Exon 65 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.4907C>T	p.Pro1636Leu	missense	Exon 64 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2813 AN: 152178 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0203 AC: 4962 AN: 244856 AF XY: 0.0202

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.00148

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0197 AC: 28847 AN: 1460772 Hom.: 466 Cov.: 31 AF XY: 0.0201 AC XY: 14627 AN XY: 726704

African (AFR) AF: 0.00349 AC: 117 AN: 33480

American (AMR) AF: 0.0111 AC: 498 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2755 AN: 26136

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39700

South Asian (SAS) AF: 0.00872 AC: 752 AN: 86258

European-Finnish (FIN) AF: 0.0216 AC: 1129 AN: 52316

Middle Eastern (MID) AF: 0.0395 AC: 228 AN: 5768

European-Non Finnish (NFE) AF: 0.0197 AC: 21902 AN: 1112004

Other (OTH) AF: 0.0237 AC: 1434 AN: 60386

GnomAD4 genome AF: 0.0185 AC: 2813 AN: 152296 Hom.: 69 Cov.: 32 AF XY: 0.0181 AC XY: 1349 AN XY: 74464

African (AFR) AF: 0.00274 AC: 114 AN: 41576

American (AMR) AF: 0.0188 AC: 287 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 411 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4826

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10620

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0244 AC: 1659 AN: 68010

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0242 Hom.: 287

Bravo AF: 0.0170

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00298 AC: 9

ESP6500EA AF: 0.0255 AC: 138

ExAC AF: 0.0191 AC: 2262

Asia WGS AF: 0.00520 AC: 20 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0231

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Connective tissue disorder (1)
-	-	1	Fibrochondrogenesis 2 (1)
-	-	1	Otospondylomegaepiphyseal dysplasia, autosomal dominant (1)
-	-	1	Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)
-	-	1	Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.80
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0070	D
Vest4		0.15
MPC		0.34
ClinPred		0.023	T
GERP RS		4.1
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229792; hg19: chr6-33131501; COSMIC: COSV108877632;