rs146522169

Variant names:

• chr6-33188451-G-A
• rs146522169
• NM_080680.3:c.517C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-33188451-G-A
• chr6-33188451-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001424109.1(COL11A2):​c.-330C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: COL11A2 NM_001424109.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.40
• Publications: 6 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022455275).
• BP6: Variant 6-33188451-G-A is Benign according to our data. Variant chr6-33188451-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228538.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000499 (76/152218) while in subpopulation AMR AF = 0.00137 (21/15296). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424109.1. 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.517C>T	p.Arg173Trp	missense	Exon 4 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424109.1		c.-330C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 66	NP_001411038.1
	COL11A2	NM_001424110.1		c.-330C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 65	NP_001411039.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.517C>T	p.Arg173Trp	missense	Exon 4 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000395194.1	TSL:1	c.517C>T	p.Arg173Trp	missense	Exon 4 of 5	ENSP00000378620.1	P13942-9
	COL11A2	ENST00000930122.1		c.517C>T	p.Arg173Trp	missense	Exon 4 of 65	ENSP00000600181.1

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000158 AC: 39 AN: 246566 AF XY: 0.000126

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460764 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 726692

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.000380 AC: 17 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: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52306

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

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112008

Other (OTH) AF: 0.000116 AC: 7 AN: 60384

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74430

African (AFR) AF: 0.00125 AC: 52 AN: 41522

American (AMR) AF: 0.00137 AC: 21 AN: 15296

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

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: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000706

ESP6500AA AF: 0.000662 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000195 AC: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.14
Sift	Benign	0.097	T
Sift4G	Uncertain	0.0050	D
Vest4		0.57
MVP		0.46
MPC		1.1
ClinPred		0.076	T
GERP RS		2.8
gMVP		0.56
Mutation Taster		=80/20	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: rs146522169; hg19: chr6-33156228;