6-33174229-C-T

Variant names:

• chr6-33174229-C-T
• rs368695514
• NM_080680.3:c.2431-11G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_080680.3(COL11A2):​c.2431-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,554,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Scores: Splicing: ADA: 0.00001809
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.36

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-33174229-C-T is Benign according to our data. Variant chr6-33174229-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000421 (61/145016) while in subpopulation AFR AF= 0.000979 (37/37788). AF 95% confidence interval is 0.00073. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.2431-11G>A		intron_variant	Intron 31 of 65	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.2431-11G>A		intron_variant	Intron 31 of 65	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2173-11G>A		intron_variant	Intron 29 of 63	5		ENSP00000363840.4
COL11A2	ENST00000361917.6	c.1003-11G>A		intron_variant	Intron 18 of 23	5		ENSP00000355123.2
COL11A2	ENST00000477772.1	n.272+2780G>A		intron_variant	Intron 5 of 8	2

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 61 AN: 145016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000336

Gnomad ASJ AF: 0.00293

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000136

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 46 AN: 162034 Hom.: 0 AF XY: 0.000263 AC XY: 23 AN XY: 87386

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000189

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000159 AC: 224 AN: 1409124 Hom.: 0 Cov.: 41 AF XY: 0.000164 AC XY: 114 AN XY: 696210

Gnomad4 AFR exome AF: 0.000659

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00202

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.0000408

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000343

GnomAD4 genome AF: 0.000421 AC: 61 AN: 145016 Hom.: 0 Cov.: 32 AF XY: 0.000424 AC XY: 30 AN XY: 70694

Gnomad4 AFR AF: 0.000979

Gnomad4 AMR AF: 0.000336

Gnomad4 ASJ AF: 0.00293

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000136

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000397

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Feb 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL11A2 c.2431-11G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 162034 control chromosomes. This frequency does not allow for any conclusion about variant significance. To our knowledge, no occurrence of c.2431-11G>A in individuals affected with COL11A2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 227265). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 27, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2431-11G>A in intron 31 of COL11A2: This variant is not expected to have clini cal significance because the nucleotide at position c.2431-11 is not conserved t hrough species, with many species having an adenine (A) at this position. In add ition, this variant is not predicted to impact splicing, and it has been identif ied in 8/9116 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs368695514). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs368695514; hg19: chr6-33142006;