chr6-33170061-G-C

Position:

• chr6-33170061-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_080680.3(COL11A2):​c.3622C>G​(p.Pro1208Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.610

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054613054).
• BP6: Variant 6-33170061-G-C is Benign according to our data. Variant chr6-33170061-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1518020.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000138 (21/152244) while in subpopulation AFR AF= 0.000458 (19/41516). AF 95% confidence interval is 0.000299. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.3622C>G	p.Pro1208Ala	missense_variant	49/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.3622C>G	p.Pro1208Ala	missense_variant	49/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.3364C>G	p.Pro1122Ala	missense_variant	47/64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.273-4245C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000526 AC: 13 AN: 247216 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134574

Gnomad AFR exome AF: 0.000328

Gnomad AMR exome AF: 0.000203

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460790 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 726710

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74450

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.000121

ExAC AF: 0.0000501 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.010	T;T;.
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.15	N
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Uncertain	0.44	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.59	T;T;T
Vest4		0.19
MutPred		0.45		.;Loss of catalytic residue at P1208 (P = 0.0231);.;
MVP		0.70
MPC		0.33
ClinPred		0.059	T
GERP RS		4.5
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs374515005; hg19: chr6-33137838;