6-33174020-C-T

Variant names:

• chr6-33174020-C-T
• rs117237998
• NM_080680.3:c.2520G>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.2520G>A​(p.Arg840Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,972 control chromosomes in the GnomAD database, including 232 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. R840R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (209 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.633
• Publications: 3 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 6-33174020-C-T is Benign according to our data. Variant chr6-33174020-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.633 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00294 (447/152170) while in subpopulation EAS AF = 0.0518 (267/5154). AF 95% confidence interval is 0.0467. There are 23 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.2520G>A	p.Arg840Arg	synonymous	Exon 33 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2340G>A	p.Arg780Arg	synonymous	Exon 32 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.2262G>A	p.Arg754Arg	synonymous	Exon 31 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.2520G>A	p.Arg840Arg	synonymous	Exon 33 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2340G>A	p.Arg780Arg	synonymous	Exon 32 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2262G>A	p.Arg754Arg	synonymous	Exon 31 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 152052 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00523 AC: 1312 AN: 250890 AF XY: 0.00518

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0518

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00192 AC: 2807 AN: 1461802 Hom.: 209 Cov.: 37 AF XY: 0.00199 AC XY: 1450 AN XY: 727210

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0269 AC: 1066 AN: 39700

South Asian (SAS) AF: 0.00963 AC: 831 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111998

Other (OTH) AF: 0.0141 AC: 850 AN: 60394

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152170 Hom.: 23 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74392

African (AFR) AF: 0.000916 AC: 38 AN: 41504

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0518 AC: 267 AN: 5154

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.00272

Asia WGS AF: 0.0500 AC: 175 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.30
CADD	Benign	8.2
DANN	Benign	0.70
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs117237998; hg19: chr6-33141797; COSMIC: COSV59497427; COSMIC: COSV59497427;