rs146093235

Variant names:

• chr6-33171752-C-A
• rs146093235
• NM_080680.3:c.3111G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-33171752-C-A
• chr6-33171752-C-T

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.3111G>T​(p.Pro1037Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,612,914 control chromosomes in the GnomAD database, including 93 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. P1037P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (87 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -6.05
• 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=-0.37).
• BP6: Variant 6-33171752-C-A is Benign according to our data. Variant chr6-33171752-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00162 (247/152248) while in subpopulation SAS AF = 0.0334 (161/4822). AF 95% confidence interval is 0.0292. There are 6 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.3111G>T	p.Pro1037Pro	synonymous	Exon 42 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2931G>T	p.Pro977Pro	synonymous	Exon 41 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.2853G>T	p.Pro951Pro	synonymous	Exon 40 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.3111G>T	p.Pro1037Pro	synonymous	Exon 42 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2931G>T	p.Pro977Pro	synonymous	Exon 41 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2853G>T	p.Pro951Pro	synonymous	Exon 40 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152130 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00446 AC: 1094 AN: 245148 AF XY: 0.00596

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00329

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00229 AC: 3340 AN: 1460666 Hom.: 87 Cov.: 38 AF XY: 0.00327 AC XY: 2373 AN XY: 726654

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26132

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39698

South Asian (SAS) AF: 0.0328 AC: 2825 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111962

Other (OTH) AF: 0.00441 AC: 266 AN: 60372

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152248 Hom.: 6 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74444

African (AFR) AF: 0.000866 AC: 36 AN: 41552

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5168

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67990

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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	-0.37
CADD	Benign	0.12
DANN	Benign	0.71
PhyloP100		-6.1
Mutation Taster		=100/0	polymorphism

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: rs146093235; hg19: chr6-33139529; COSMIC: COSV59496790;