rs375268140

Positions:

• chr6-33189196-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_080680.3(COL11A2):​c.233-8G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: COL11A2 NM_080680.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001013
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.657

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-33189196-C-A is Benign according to our data. Variant chr6-33189196-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228533.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.233-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.233-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_080680.3	ENSP00000339915	P4
COL11A2	ENST00000395194.1	c.233-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000378620
COL11A2	ENST00000374708.8	c.233-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000363840	A1
COL11A2	ENST00000682718.1	n.50-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249232 Hom.: 0 AF XY: 0.0000890 AC XY: 12 AN XY: 134906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 280 AN: 1461440 Hom.: 0 Cov.: 33 AF XY: 0.000199 AC XY: 145 AN XY: 726984

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74296

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000147

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	COL11A2: PM2, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2015

Variant classified as Uncertain Significance - Favor Benign. The c.233-8G>T vari ant in COLL11A2 has not been reported in individuals with hearing loss or Stickl er syndrome. It has been identified in 13/64704 of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs37526 8140); however this frequency is not high enough to rule out a pathogenic role. The variant occurs in the 3' splice region but does not impact the invariant (-1 /-2) positions of the splice consensus sequence. Computational tools do not sugg est an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.23 3-8G>T variant is uncertain, these data suggest that it is more likely to be ben ign. -

COL11A2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.022
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

Publications

LitVar

Other links and lift over

dbSNP: rs375268140; hg19: chr6-33156973;