2-237361149-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP6

The NM_004369.4(COL6A3):​c.6182G>A​(p.Arg2061Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

10
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.76

Publications

5 publications found
Variant links:
Genes affected
COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]
COL6A3 Gene-Disease associations (from GenCC):
  • Bethlem myopathy 1A
    Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
  • collagen 6-related myopathy
    Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
  • Ullrich congenital muscular dystrophy 1C
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • dystonia 27
    Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
  • Ullrich congenital muscular dystrophy 1A
    Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
  • Bethlem myopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Ullrich congenital muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004369.4
BP6
Variant 2-237361149-C-T is Benign according to our data. Variant chr2-237361149-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476545.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A3NM_004369.4 linkc.6182G>A p.Arg2061Gln missense_variant Exon 16 of 44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3NM_057167.4 linkc.5564G>A p.Arg1855Gln missense_variant Exon 15 of 43 NP_476508.2 P12111-2Q8N4Z1Q63HQ4
COL6A3NM_057166.5 linkc.4361G>A p.Arg1454Gln missense_variant Exon 13 of 41 NP_476507.3 P12111-4B7ZW00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkc.6182G>A p.Arg2061Gln missense_variant Exon 16 of 44 1 NM_004369.4 ENSP00000295550.4 P12111-1
COL6A3ENST00000472056.5 linkc.4361G>A p.Arg1454Gln missense_variant Exon 13 of 41 1 ENSP00000418285.1 P12111-4
COL6A3ENST00000353578.9 linkc.5564G>A p.Arg1855Gln missense_variant Exon 15 of 43 5 ENSP00000315873.4 P12111-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251450
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461832
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
727218
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000216
AC:
24
AN:
1111976
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.6182G>A (p.R2061Q) alteration is located in exon 16 (coding exon 15) of the COL6A3 gene. This alteration results from a G to A substitution at nucleotide position 6182, causing the arginine (R) at amino acid position 2061 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 1A Benign:1
Jun 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
0.0037
T
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
.;T;.;T;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D;D;D;.
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.59
D;D;D;D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Benign
0.13
.;N;.;.;.
PhyloP100
2.8
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.88
N;N;N;.;N
REVEL
Uncertain
0.44
Sift
Benign
0.25
T;T;T;.;T
Sift4G
Benign
0.16
T;T;T;T;T
Polyphen
1.0
D;P;.;.;D
Vest4
0.56
MVP
0.88
MPC
0.68
ClinPred
0.78
D
GERP RS
5.2
Varity_R
0.19
gMVP
0.30
Mutation Taster
=80/20
polymorphism

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

Other links and lift over

dbSNP: rs376715966; hg19: chr2-238269792; COSMIC: COSV55088295; COSMIC: COSV55088295; API