NM_080680.3:c.2584-5delC

Variant names:

• chr6-33173749-TG-T
• rs555657704
• NM_080680.3:c.2584-5delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_080680.3(COL11A2):​c.2584-5delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,594,094 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: COL11A2 NM_080680.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.994
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 6-33173749-TG-T is Benign according to our data. Variant chr6-33173749-TG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (160/151480) while in subpopulation NFE AF = 0.00196 (133/67788). AF 95% confidence interval is 0.00169. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2584-5delC		splice_region intron	N/A	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2404-5delC		splice_region intron	N/A	NP_001411037.1
	COL11A2	NM_080681.3		c.2326-5delC		splice_region intron	N/A	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.2584-5delC		splice_region intron	N/A	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2404-5delC		splice_region intron	N/A	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2326-5delC		splice_region intron	N/A	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 160 AN: 151362 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000760

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00124 AC: 298 AN: 239644 AF XY: 0.00134

Gnomad AFR exome AF: 0.000382

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00148 AC: 2141 AN: 1442614 Hom.: 4 Cov.: 36 AF XY: 0.00143 AC XY: 1023 AN XY: 714712

African (AFR) AF: 0.000152 AC: 5 AN: 32992

American (AMR) AF: 0.000458 AC: 20 AN: 43674

Ashkenazi Jewish (ASJ) AF: 0.000441 AC: 11 AN: 24930

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39384

South Asian (SAS) AF: 0.000322 AC: 27 AN: 83800

European-Finnish (FIN) AF: 0.00127 AC: 67 AN: 52674

Middle Eastern (MID) AF: 0.00246 AC: 14 AN: 5682

European-Non Finnish (NFE) AF: 0.00174 AC: 1919 AN: 1100044

Other (OTH) AF: 0.00128 AC: 76 AN: 59434

GnomAD4 genome AF: 0.00106 AC: 160 AN: 151480 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 76 AN XY: 74034

African (AFR) AF: 0.000218 AC: 9 AN: 41208

American (AMR) AF: 0.000262 AC: 4 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4796

European-Finnish (FIN) AF: 0.000760 AC: 8 AN: 10528

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

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67788

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Fibrochondrogenesis 1 (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
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs555657704; hg19: chr6-33141526;