chr6-33184166-C-T

Variant names:

• chr6-33184166-C-T
• rs73741539
• NM_080680.3:c.1098G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_080680.3(COL11A2):​c.1098G>A​(p.Ala366Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,367,306 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. A366A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (12 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0380
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 6-33184166-C-T is Benign according to our data. Variant chr6-33184166-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.038 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00619 (943/152272) while in subpopulation AFR AF = 0.018 (748/41542). AF 95% confidence interval is 0.0169. There are 4 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1098G>A	p.Ala366Ala	synonymous	Exon 8 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424109.1		c.252G>A	p.Ala84Ala	synonymous	Exon 8 of 66	NP_001411038.1
	COL11A2	NM_001424108.1		c.939+826G>A		intron	N/A	NP_001411037.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.1098G>A	p.Ala366Ala	synonymous	Exon 8 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.939+826G>A		intron	N/A	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.861+826G>A		intron	N/A	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 943 AN: 152156 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00260 AC: 651 AN: 250832 AF XY: 0.00213

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00197 AC: 2393 AN: 1215034 Hom.: 12 Cov.: 31 AF XY: 0.00189 AC XY: 1140 AN XY: 602136

African (AFR) AF: 0.0198 AC: 521 AN: 26300

American (AMR) AF: 0.00485 AC: 181 AN: 37290

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 2 AN: 16896

East Asian (EAS) AF: 0.00 AC: 0 AN: 16806

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83226

European-Finnish (FIN) AF: 0.0000624 AC: 2 AN: 32050

Middle Eastern (MID) AF: 0.00291 AC: 13 AN: 4474

European-Non Finnish (NFE) AF: 0.00164 AC: 1565 AN: 953972

Other (OTH) AF: 0.00225 AC: 99 AN: 44020

GnomAD4 genome AF: 0.00619 AC: 943 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74446

African (AFR) AF: 0.0180 AC: 748 AN: 41542

American (AMR) AF: 0.00445 AC: 68 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68028

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00332 Hom.: 2

Bravo AF: 0.00714

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	-0.30
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73741539; hg19: chr6-33151943; COSMIC: COSV59502751; COSMIC: COSV59502751;