21-46126225-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001849.4(COL6A2):​c.2410G>C​(p.Val804Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V804G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

COL6A2
NM_001849.4 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.59
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a domain VWFA 2 (size 190) in uniprot entity CO6A2_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_001849.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27074933).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.2410G>C p.Val804Leu missense_variant Exon 26 of 28 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3
COL6A2NM_058174.3 linkc.2410G>C p.Val804Leu missense_variant Exon 26 of 28 NP_478054.2 P12110-2
COL6A2NM_058175.3 linkc.2410G>C p.Val804Leu missense_variant Exon 26 of 28 NP_478055.2 P12110-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.2410G>C p.Val804Leu missense_variant Exon 26 of 28 1 NM_001849.4 ENSP00000300527.4 P12110-1
COL6A2ENST00000397763.6 linkc.2410G>C p.Val804Leu missense_variant Exon 26 of 28 5 ENSP00000380870.1 P12110-2
COL6A2ENST00000409416.6 linkc.2410G>C p.Val804Leu missense_variant Exon 25 of 27 5 ENSP00000387115.1 P12110-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
16
DANN
Benign
0.71
DEOGEN2
Benign
0.19
T;.;.;.
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.47
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D;D;.;D
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.27
T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.4
M;M;M;M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.91
N;N;N;N
REVEL
Benign
0.18
Sift
Benign
0.64
T;T;T;T
Sift4G
Benign
0.64
T;T;T;T
Polyphen
0.038
B;B;B;B
Vest4
0.45
MutPred
0.33
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
0.72
MPC
0.14
ClinPred
0.53
D
GERP RS
1.4
Varity_R
0.082
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs199896699; hg19: chr21-47546139; API