chr6-33171698-T-G

Variant names:

• chr6-33171698-T-G
• rs2855436
• NM_080680.3:c.3150+15A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080680.3(COL11A2):​c.3150+15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,598,854 control chromosomes in the GnomAD database, including 449,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47178 hom., cov: 29)
  • Exomes 𝑓: 0.74 (401926 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.51
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-33171698-T-G is Benign according to our data. Variant chr6-33171698-T-G is described in ClinVar as Benign. ClinVar VariationId is 46564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

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.3150+15A>C		intron	N/A	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2970+15A>C		intron	N/A	NP_001411037.1
	COL11A2	NM_080681.3		c.2892+15A>C		intron	N/A	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.3150+15A>C		intron	N/A	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2970+15A>C		intron	N/A	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2892+15A>C		intron	N/A	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.784 AC: 118921 AN: 151606 Hom.: 47131 Cov.: 29

Gnomad AFR AF: 0.874

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.784 AC: 189272 AN: 241478 AF XY: 0.786

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.801

Gnomad ASJ exome AF: 0.812

Gnomad EAS exome AF: 0.976

Gnomad FIN exome AF: 0.699

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.744 AC: 1076944 AN: 1447130 Hom.: 401926 Cov.: 36 AF XY: 0.749 AC XY: 539148 AN XY: 720254

African (AFR) AF: 0.886 AC: 29547 AN: 33352

American (AMR) AF: 0.802 AC: 35708 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 21146 AN: 26056

East Asian (EAS) AF: 0.983 AC: 38959 AN: 39646

South Asian (SAS) AF: 0.890 AC: 76530 AN: 86004

European-Finnish (FIN) AF: 0.706 AC: 36566 AN: 51818

Middle Eastern (MID) AF: 0.831 AC: 4786 AN: 5756

European-Non Finnish (NFE) AF: 0.716 AC: 787929 AN: 1100128

Other (OTH) AF: 0.765 AC: 45773 AN: 59872

GnomAD4 genome AF: 0.784 AC: 119024 AN: 151724 Hom.: 47178 Cov.: 29 AF XY: 0.785 AC XY: 58236 AN XY: 74144

African (AFR) AF: 0.874 AC: 36198 AN: 41418

American (AMR) AF: 0.788 AC: 12037 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3472

East Asian (EAS) AF: 0.972 AC: 4986 AN: 5130

South Asian (SAS) AF: 0.907 AC: 4346 AN: 4794

European-Finnish (FIN) AF: 0.711 AC: 7458 AN: 10492

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48718 AN: 67830

Other (OTH) AF: 0.802 AC: 1693 AN: 2110

Alfa AF: 0.745 Hom.: 18199

Bravo AF: 0.794

Asia WGS AF: 0.904 AC: 3140 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Fibrochondrogenesis 2 (2)
-	-	2	Otospondylomegaepiphyseal dysplasia, autosomal dominant (2)
-	-	2	Otospondylomegaepiphyseal dysplasia, autosomal recessive (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 13 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 53 (1)
-	-	1	not provided (1)
-	-	1	Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.31
DANN	Benign	0.33
PhyloP100		-1.5
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: rs2855436; hg19: chr6-33139475;