NM_080680.3:c.3313-11C>T

Variant names:

• chr6-33171178-G-A
• rs2855437
• NM_080680.3:c.3313-11C>T

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.3313-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,610,246 control chromosomes in the GnomAD database, including 409,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41958 hom., cov: 31)
  • Exomes 𝑓: 0.71 (367758 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Scores: Splicing: ADA: 0.00001617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.398
• Publications: 32 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, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.82).
• BP6: Variant 6-33171178-G-A is Benign according to our data. Variant chr6-33171178-G-A is described in ClinVar as Benign. ClinVar VariationId is 46566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	NM_080680.3	MANE Select	c.3313-11C>T		intron	N/A	NP_542411.2
	COL11A2	NM_001424108.1		c.3133-11C>T		intron	N/A	NP_001411037.1
	COL11A2	NM_080681.3		c.3055-11C>T		intron	N/A	NP_542412.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.3313-11C>T		intron	N/A	ENSP00000339915.2
	COL11A2	ENST00000374708.8	TSL:5	c.3055-11C>T		intron	N/A	ENSP00000363840.4
	COL11A2	ENST00000477772.1	TSL:2	n.273-5362C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112418 AN: 151924 Hom.: 41911 Cov.: 31

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.783

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.744 AC: 181785 AN: 244222 AF XY: 0.746

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.765

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.734

GnomAD4 exome AF: 0.708 AC: 1031882 AN: 1458204 Hom.: 367758 Cov.: 61 AF XY: 0.711 AC XY: 515820 AN XY: 725120

African (AFR) AF: 0.814 AC: 27207 AN: 33440

American (AMR) AF: 0.765 AC: 33695 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 19995 AN: 26054

East Asian (EAS) AF: 0.945 AC: 37478 AN: 39660

South Asian (SAS) AF: 0.825 AC: 70879 AN: 85920

European-Finnish (FIN) AF: 0.695 AC: 37007 AN: 53258

Middle Eastern (MID) AF: 0.785 AC: 4519 AN: 5760

European-Non Finnish (NFE) AF: 0.683 AC: 758229 AN: 1109794

Other (OTH) AF: 0.711 AC: 42873 AN: 60286

GnomAD4 genome AF: 0.740 AC: 112521 AN: 152042 Hom.: 41958 Cov.: 31 AF XY: 0.741 AC XY: 55112 AN XY: 74332

African (AFR) AF: 0.801 AC: 33219 AN: 41468

American (AMR) AF: 0.742 AC: 11361 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2635 AN: 3470

East Asian (EAS) AF: 0.900 AC: 4626 AN: 5138

South Asian (SAS) AF: 0.828 AC: 3992 AN: 4824

European-Finnish (FIN) AF: 0.701 AC: 7430 AN: 10594

Middle Eastern (MID) AF: 0.791 AC: 231 AN: 292

European-Non Finnish (NFE) AF: 0.691 AC: 46924 AN: 67930

Other (OTH) AF: 0.744 AC: 1572 AN: 2112

Alfa AF: 0.712 Hom.: 153058

Bravo AF: 0.745

Asia WGS AF: 0.818 AC: 2844 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.82
CADD	Benign	2.9
DANN	Benign	0.41
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs2855437; hg19: chr6-33138955;