rs142969513

Variant names:

• chr6-33188488-A-C
• rs142969513
• NM_080680.3:c.480T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-33188488-A-C
• chr6-33188488-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_080680.3(COL11A2):​c.480T>G​(p.Ser160Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,613,070 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S160S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.529
• Publications: 0 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

ENSG00000305994 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-33188488-A-C is Benign according to our data. Variant chr6-33188488-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197366.
• BP7: Synonymous conserved (PhyloP=-0.529 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00044 (67/152308) while in subpopulation NFE AF = 0.000911 (62/68030). AF 95% confidence interval is 0.000729. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.480T>G	p.Ser160Ser	synonymous	Exon 4 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.480T>G	p.Ser160Ser	synonymous	Exon 4 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.480T>G	p.Ser160Ser	synonymous	Exon 4 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.480T>G	p.Ser160Ser	synonymous	Exon 4 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000395194.1	TSL:1	c.480T>G	p.Ser160Ser	synonymous	Exon 4 of 5	ENSP00000378620.1	P13942-9
	COL11A2	ENST00000930122.1		c.480T>G	p.Ser160Ser	synonymous	Exon 4 of 65	ENSP00000600181.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000926

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000430 AC: 106 AN: 246564 AF XY: 0.000394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000931

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000496 AC: 725 AN: 1460762 Hom.: 2 Cov.: 32 AF XY: 0.000516 AC XY: 375 AN XY: 726698

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000635 AC: 706 AN: 1112002

Other (OTH) AF: 0.000199 AC: 12 AN: 60384

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74486

African (AFR) AF: 0.0000963 AC: 4 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

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

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.000446

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	COL11A2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.1
DANN	Benign	0.70
PhyloP100		-0.53
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: rs142969513; hg19: chr6-33156265;