rs41266697

Variant names:

• chr6-33178344-G-A
• rs41266697
• NM_080680.3:c.1782C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_080680.3(COL11A2):​c.1782C>T​(p.Asp594Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,612,264 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (52 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0930
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-33178344-G-A is Benign according to our data. Variant chr6-33178344-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.093 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00675 (1023/151514) while in subpopulation NFE AF = 0.00747 (507/67836). AF 95% confidence interval is 0.00694. There are 8 homozygotes in GnomAd4. There are 460 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.1782C>T	p.Asp594Asp	synonymous	Exon 20 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.1602C>T	p.Asp534Asp	synonymous	Exon 19 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.1524C>T	p.Asp508Asp	synonymous	Exon 18 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.1782C>T	p.Asp594Asp	synonymous	Exon 20 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.1602C>T	p.Asp534Asp	synonymous	Exon 19 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.1524C>T	p.Asp508Asp	synonymous	Exon 18 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1023 AN: 151398 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00546

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00583

Gnomad FIN AF: 0.00409

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00690 AC: 1702 AN: 246628 AF XY: 0.00689

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.00473

Gnomad ASJ exome AF: 0.0213

Gnomad EAS exome AF: 0.000602

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.00741

GnomAD4 exome AF: 0.00765 AC: 11172 AN: 1460750 Hom.: 52 Cov.: 35 AF XY: 0.00764 AC XY: 5553 AN XY: 726694

African (AFR) AF: 0.00582 AC: 195 AN: 33480

American (AMR) AF: 0.00467 AC: 209 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 542 AN: 26134

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.00750 AC: 647 AN: 86258

European-Finnish (FIN) AF: 0.00483 AC: 253 AN: 52332

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.00793 AC: 8819 AN: 1111978

Other (OTH) AF: 0.00768 AC: 464 AN: 60386

GnomAD4 genome AF: 0.00675 AC: 1023 AN: 151514 Hom.: 8 Cov.: 32 AF XY: 0.00621 AC XY: 460 AN XY: 74036

African (AFR) AF: 0.00645 AC: 266 AN: 41234

American (AMR) AF: 0.00545 AC: 83 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3462

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5122

South Asian (SAS) AF: 0.00584 AC: 28 AN: 4796

European-Finnish (FIN) AF: 0.00409 AC: 43 AN: 10522

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00747 AC: 507 AN: 67836

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00776 Hom.: 5

Bravo AF: 0.00646

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	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
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.89
DANN	Benign	0.41
PhyloP100		0.093
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41266697; hg19: chr6-33146121;