NM_080680.3:c.2628+3G>A

Variant names:

• chr6-33173698-C-T
• rs970901
• NM_080680.3:c.2628+3G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080680.3(COL11A2):​c.2628+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,565,514 control chromosomes in the GnomAD database, including 254,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26065 hom., cov: 28)
  • Exomes 𝑓: 0.56 (228645 hom.)
• Consequence: COL11A2 NM_080680.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001475
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.23
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-33173698-C-T is Benign according to our data. Variant chr6-33173698-C-T is described in ClinVar as Benign. ClinVar VariationId is 46560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

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.2628+3G>A		splice_region intron	N/A	NP_542411.2	A0A0C4DFS1
	COL11A2	NM_001424108.1		c.2448+3G>A		splice_region intron	N/A	NP_001411037.1
	COL11A2	NM_080681.3		c.2370+3G>A		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.2628+3G>A		splice_region intron	N/A	ENSP00000339915.2	A0A0C4DFS1
	COL11A2	ENST00000930122.1		c.2448+3G>A		splice_region intron	N/A	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.2370+3G>A		splice_region intron	N/A	ENSP00000363840.4	Q4VXY6

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88095 AN: 150868 Hom.: 26050 Cov.: 28

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.607

GnomAD2 exomes AF: 0.604 AC: 127922 AN: 211774 AF XY: 0.601

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.809

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.565 AC: 798514 AN: 1414528 Hom.: 228645 Cov.: 39 AF XY: 0.567 AC XY: 395908 AN XY: 698330

African (AFR) AF: 0.618 AC: 19940 AN: 32268

American (AMR) AF: 0.683 AC: 27876 AN: 40800

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 15385 AN: 22934

East Asian (EAS) AF: 0.833 AC: 32700 AN: 39276

South Asian (SAS) AF: 0.629 AC: 49486 AN: 78686

European-Finnish (FIN) AF: 0.517 AC: 26263 AN: 50786

Middle Eastern (MID) AF: 0.649 AC: 3583 AN: 5524

European-Non Finnish (NFE) AF: 0.543 AC: 590248 AN: 1086028

Other (OTH) AF: 0.567 AC: 33033 AN: 58226

GnomAD4 genome AF: 0.584 AC: 88142 AN: 150986 Hom.: 26065 Cov.: 28 AF XY: 0.584 AC XY: 43039 AN XY: 73742

African (AFR) AF: 0.595 AC: 24442 AN: 41082

American (AMR) AF: 0.641 AC: 9754 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2341 AN: 3466

East Asian (EAS) AF: 0.788 AC: 3941 AN: 5002

South Asian (SAS) AF: 0.633 AC: 3030 AN: 4784

European-Finnish (FIN) AF: 0.518 AC: 5429 AN: 10482

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37238 AN: 67654

Other (OTH) AF: 0.610 AC: 1278 AN: 2096

Alfa AF: 0.572 Hom.: 64694

Bravo AF: 0.595

Asia WGS AF: 0.677 AC: 2357 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Fibrochondrogenesis 2 (2)
-	-	2	Otospondylomegaepiphyseal dysplasia, autosomal dominant (2)
-	-	2	Otospondylomegaepiphyseal dysplasia, autosomal recessive (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 13 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 53 (1)
-	-	1	not provided (1)
-	-	1	Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.71
PhyloP100		1.2
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs970901; hg19: chr6-33141475;