rs376797260

Variant names:

• chr6-33172356-G-A
• rs376797260
• NM_080680.3:c.2921C>T

Variant summary

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

The NM_080680.3(COL11A2):​c.2921C>T​(p.Ala974Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,588,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A974A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 1.13
• 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053055078).
• BP6: Variant 6-33172356-G-A is Benign according to our data. Variant chr6-33172356-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178927.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000158 (24/151816) while in subpopulation NFE AF = 0.000339 (23/67870). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 10 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_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.2921C>T	p.Ala974Val	missense	Exon 40 of 66	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2741C>T	p.Ala914Val	missense	Exon 39 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.2663C>T	p.Ala888Val	missense	Exon 38 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.2921C>T	p.Ala974Val	missense	Exon 40 of 66	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2741C>T	p.Ala914Val	missense	Exon 39 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2663C>T	p.Ala888Val	missense	Exon 38 of 64	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151698 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

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: 0.000339

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000997 AC: 20 AN: 200506 AF XY: 0.000101

Gnomad AFR exome AF: 0.0000875

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000286 AC: 411 AN: 1436564 Hom.: 0 Cov.: 33 AF XY: 0.000277 AC XY: 197 AN XY: 712132

African (AFR) AF: 0.0000602 AC: 2 AN: 33210

American (AMR) AF: 0.0000249 AC: 1 AN: 40216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25506

East Asian (EAS) AF: 0.00 AC: 0 AN: 38862

South Asian (SAS) AF: 0.00 AC: 0 AN: 82680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000364 AC: 401 AN: 1100234

Other (OTH) AF: 0.000118 AC: 7 AN: 59480

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151816 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74208

African (AFR) AF: 0.0000242 AC: 1 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.0000515 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)
-	1	-	Fibrochondrogenesis 2 (1)
-	1	-	not specified (1)
-	1	-	Otospondylomegaepiphyseal dysplasia, autosomal dominant (1)
-	1	-	Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)
-	-	-	Otospondylomegaepiphyseal dysplasia, autosomal dominant;C1864746:Autosomal recessive nonsyndromic hearing loss 53;C1866095:Autosomal dominant nonsyndromic hearing loss 13;C3281128:Fibrochondrogenesis 2;CN034493:Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.62	T
PhyloP100		1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.23
Sift	Benign	0.32	T
Sift4G	Benign	0.38	T
Vest4		0.17
MVP		0.40
MPC		0.82
ClinPred		0.12	T
GERP RS		4.5
gMVP		0.14
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs376797260; hg19: chr6-33140133;