chr6-33188424-C-T

Position:

• chr6-33188424-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_080680.3(COL11A2):​c.544G>A​(p.Val182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (1 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.0960

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL11A2. . Gene score misZ 2.3685 (greater than the threshold 3.09). Trascript score misZ 3.3886 (greater than threshold 3.09). GenCC has associacion of gene with otospondylomegaepiphyseal dysplasia, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss, autosomal recessive nonsyndromic hearing loss 53, otospondylomegaepiphyseal dysplasia, autosomal dominant, nonsyndromic genetic hearing loss, fibrochondrogenesis, hearing loss, autosomal recessive, otospondylomegaepiphyseal dysplasia, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01955533).
• BP6: Variant 6-33188424-C-T is Benign according to our data. Variant chr6-33188424-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr6-33188424-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.544G>A	p.Val182Ile	missense_variant	4/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.544G>A	p.Val182Ile	missense_variant	4/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000395194.1	c.544G>A	p.Val182Ile	missense_variant	4/5	1		ENSP00000378620.1
COL11A2	ENST00000374708.8	c.544G>A	p.Val182Ile	missense_variant	4/64	5		ENSP00000363840.4
COL11A2	ENST00000682718.1	n.361G>A		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000487 AC: 12 AN: 246594 Hom.: 1 AF XY: 0.0000298 AC XY: 4 AN XY: 134422

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000493

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1460772 Hom.: 1 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 726700

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74426

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Bravo AF: 0.0000529

ExAC AF: 0.0000340 AC: 4

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 30, 2023	The COL11A2 c.544G>A; p.Val182Ile variant (rs375937729), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 547213). This variant is found in the East Asian population with an allele frequency of 0.05% (9/18274 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.06). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Val182Ile var iant in COL11A2 has not been previously reported in individuals with hearing los s or COL11A2-related syndromes. This variant has been identified in 8/17130 East Asian chromosomes, including one homozygous individual, by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375937729). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. The valine (Val) at position 182 is no t highly conserved in mammals and evolutionary distant species, and two mammals (opossum and tasmanian devil) carry an isoleucine (Ile) at this position, which suggests that a change at this position may be tolerated. Additional computation al prediction tools and conservation analysis suggest that the p.Val182Ile varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p. Val182Ile variant is uncertain, the frequency and conservation data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.544G>A (p.V182I) alteration is located in exon 4 (coding exon 4) of the COL11A2 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the valine (V) at amino acid position 182 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

COL11A2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The COL11A2 c.544G>A variant is predicted to result in the amino acid substitution p.Val182Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.049% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.26
DEOGEN2	Benign	0.14	T;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.54	.;.;.;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.28	N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.83	T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T
Vest4		0.21
MutPred		0.63		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.15
MPC		0.54
ClinPred		0.0075	T
GERP RS		2.8
gMVP		0.087

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs375937729; hg19: chr6-33156201;