2-237324809-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_004369.4(COL6A3):​c.9499G>A​(p.Ala3167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -0.552

Publications

7 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: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.029504001).
BP6
Variant 2-237324809-C-T is Benign according to our data. Variant chr2-237324809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 848577.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A3NM_004369.4 linkc.9499G>A p.Ala3167Thr missense_variant Exon 44 of 44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3NM_057167.4 linkc.8881G>A p.Ala2961Thr missense_variant Exon 43 of 43 NP_476508.2 P12111-2Q8N4Z1Q63HQ4
COL6A3NM_057166.5 linkc.7678G>A p.Ala2560Thr missense_variant Exon 41 of 41 NP_476507.3 P12111-4B7ZW00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkc.9499G>A p.Ala3167Thr missense_variant Exon 44 of 44 1 NM_004369.4 ENSP00000295550.4 P12111-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000403
AC:
10
AN:
248104
AF XY:
0.0000596
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.0000630
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000181
AC:
265
AN:
1461260
Hom.:
0
Cov.:
31
AF XY:
0.000169
AC XY:
123
AN XY:
726904
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52876
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.000231
AC:
257
AN:
1111954
Other (OTH)
AF:
0.0000994
AC:
6
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.457
Heterozygous variant carriers
0
14
27
41
54
68
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.0000394
AC:
6
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41472
American (AMR)
AF:
0.0000655
AC:
1
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.000416
AC:
2
AN:
4806
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10584
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68012
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000103
Hom.:
0
Bravo
AF:
0.0000378
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Mar 31, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Bethlem myopathy 1A Benign:1
Jan 15, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
6.2
DANN
Benign
0.76
DEOGEN2
Benign
0.13
.;T;.;T;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0064
N
LIST_S2
Benign
0.61
T;T;T;T;.
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.030
T;T;T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
-0.29
.;N;.;.;.
PhyloP100
-0.55
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.29
N;N;N;.;N
REVEL
Benign
0.18
Sift
Benign
0.15
T;T;T;.;T
Sift4G
Benign
0.37
T;T;T;T;T
Polyphen
0.0010
B;B;.;.;B
Vest4
0.070
MutPred
0.23
.;Loss of stability (P = 0.1038);.;.;.;
MVP
0.41
MPC
0.14
ClinPred
0.019
T
GERP RS
-9.9
Varity_R
0.030
gMVP
0.28
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs537511128; hg19: chr2-238233452; COSMIC: COSV55090451; API