21-46124912-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001849.4(COL6A2):​c.1762G>C​(p.Gly588Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

14
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.98
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.1762G>C p.Gly588Arg missense_variant Exon 23 of 28 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3
COL6A2NM_058174.3 linkc.1762G>C p.Gly588Arg missense_variant Exon 23 of 28 NP_478054.2 P12110-2
COL6A2NM_058175.3 linkc.1762G>C p.Gly588Arg missense_variant Exon 23 of 28 NP_478055.2 P12110-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.1762G>C p.Gly588Arg missense_variant Exon 23 of 28 1 NM_001849.4 ENSP00000300527.4 P12110-1
COL6A2ENST00000397763.6 linkc.1762G>C p.Gly588Arg missense_variant Exon 23 of 28 5 ENSP00000380870.1 P12110-2
COL6A2ENST00000409416.6 linkc.1762G>C p.Gly588Arg missense_variant Exon 22 of 27 5 ENSP00000387115.1 P12110-3
COL6A2ENST00000413758.1 linkc.385G>C p.Gly129Arg missense_variant Exon 8 of 11 3 ENSP00000395751.1 H7C0M5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460602
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
726610
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.;D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.3
H;H;H;H;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.5
D;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.023
D;D;D;D;D
Sift4G
Uncertain
0.029
D;D;D;D;D
Polyphen
1.0
D;D;D;D;.
Vest4
0.89
MutPred
0.89
Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);.;
MVP
1.0
MPC
0.67
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.93
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47544826; API