rs146555195

Variant names:

• chr6-33164337-C-T
• rs146555195
• NM_080680.3:c.5000G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-33164337-C-T
• chr6-33164337-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_080680.3(COL11A2):​c.5000G>A​(p.Arg1667His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,916 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1667C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (14 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.456
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014077336).
• BP6: Variant 6-33164337-C-T is Benign according to our data. Variant chr6-33164337-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178321.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00116 (176/152286) while in subpopulation SAS AF = 0.00559 (27/4826). AF 95% confidence interval is 0.00395. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.5000G>A	p.Arg1667His	missense	Exon 65 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.4820G>A	p.Arg1607His	missense	Exon 64 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.4742G>A	p.Arg1581His	missense	Exon 63 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.5000G>A	p.Arg1667His	missense	Exon 65 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.4820G>A	p.Arg1607His	missense	Exon 64 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.4742G>A	p.Arg1581His	missense	Exon 63 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00191 AC: 469 AN: 246086 AF XY: 0.00225

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00126 AC: 1845 AN: 1460630 Hom.: 14 Cov.: 32 AF XY: 0.00146 AC XY: 1060 AN XY: 726622

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00244 AC: 109 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00618 AC: 533 AN: 86236

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52298

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.000929 AC: 1033 AN: 1111944

Other (OTH) AF: 0.00172 AC: 104 AN: 60378

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74452

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.00222 AC: 34 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.000966 Hom.: 0

Bravo AF: 0.00123

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00148 AC: 8

ExAC AF: 0.00201 AC: 237

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 53 (1)
-	-	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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.32	N
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		0.46
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D
Sift4G	Benign	0.12	T
Vest4		0.26
MVP		0.72
MPC		0.42
ClinPred		0.011	T
GERP RS		4.9
gMVP		0.62
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: rs146555195; hg19: chr6-33132114;