21-46121563-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001849.4(COL6A2):​c.1466G>C​(p.Arg489Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R489Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.63
Variant links:
Genes affected
COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.1466G>C p.Arg489Pro missense_variant Exon 18 of 28 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3
COL6A2NM_058174.3 linkc.1466G>C p.Arg489Pro missense_variant Exon 18 of 28 NP_478054.2 P12110-2
COL6A2NM_058175.3 linkc.1466G>C p.Arg489Pro missense_variant Exon 18 of 28 NP_478055.2 P12110-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.1466G>C p.Arg489Pro missense_variant Exon 18 of 28 1 NM_001849.4 ENSP00000300527.4 P12110-1
COL6A2ENST00000397763.6 linkc.1466G>C p.Arg489Pro missense_variant Exon 18 of 28 5 ENSP00000380870.1 P12110-2
COL6A2ENST00000409416.6 linkc.1466G>C p.Arg489Pro missense_variant Exon 17 of 27 5 ENSP00000387115.1 P12110-3
COL6A2ENST00000413758.1 linkc.89G>C p.Arg30Pro missense_variant Exon 3 of 11 3 ENSP00000395751.1 H7C0M5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460512
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726562
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1
Jul 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 542990). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A2 protein function. This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 489 of the COL6A2 protein (p.Arg489Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.;.;T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.83
T;T;.;T;T
M_CAP
Pathogenic
0.31
D
MetaRNN
Uncertain
0.59
D;D;D;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
0.18
N;N;N;N;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-0.97
N;N;N;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.31
T;T;T;T;T
Sift4G
Benign
0.24
T;T;T;T;T
Polyphen
1.0
D;D;D;D;.
Vest4
0.75
MutPred
0.29
Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);.;
MVP
0.97
MPC
0.20
ClinPred
0.91
D
GERP RS
4.2
Varity_R
0.30
gMVP
0.51

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61735828; hg19: chr21-47541477; API