chr21-46132262-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001849.4(COL6A2):​c.2770G>A​(p.Ala924Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,605,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000030 ( 1 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.76

Publications

0 publications found
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]
COL6A2 Gene-Disease associations (from GenCC):
  • collagen 6-related myopathy
    Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
  • Ullrich congenital muscular dystrophy 1B
    Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
  • Bethlem myopathy 1A
    Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
  • Ullrich congenital muscular dystrophy 1A
    Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • Bethlem myopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Ullrich congenital muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • myosclerosis
    Inheritance: AR 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 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.2770G>A p.Ala924Thr missense_variant Exon 28 of 28 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.2770G>A p.Ala924Thr missense_variant Exon 28 of 28 1 NM_001849.4 ENSP00000300527.4 P12110-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152214
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000212
AC:
5
AN:
235316
AF XY:
0.0000233
show subpopulations
Gnomad AFR exome
AF:
0.0000680
Gnomad AMR exome
AF:
0.0000887
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000935
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000303
AC:
44
AN:
1453454
Hom.:
1
Cov.:
34
AF XY:
0.0000304
AC XY:
22
AN XY:
723144
show subpopulations
African (AFR)
AF:
0.0000300
AC:
1
AN:
33366
American (AMR)
AF:
0.0000676
AC:
3
AN:
44346
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26010
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39474
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85720
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48204
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5762
European-Non Finnish (NFE)
AF:
0.0000324
AC:
36
AN:
1110394
Other (OTH)
AF:
0.0000499
AC:
3
AN:
60178
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.0000460
AC:
7
AN:
152214
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41458
American (AMR)
AF:
0.000196
AC:
3
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
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:
0.0000566
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000249
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Oct 05, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 19, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 01, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Bethlem myopathy 1A Uncertain:1
May 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 924 of the COL6A2 protein (p.Ala924Thr). This variant is present in population databases (rs771749652, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542992). 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.75
T
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
1.9
L
PhyloP100
9.8
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.6
N
REVEL
Uncertain
0.61
Sift
Benign
0.030
D
Sift4G
Benign
0.18
T
Polyphen
0.96
D
Vest4
0.70
MutPred
0.71
Loss of MoRF binding (P = 0.1399);
MVP
0.93
MPC
0.60
ClinPred
0.47
T
GERP RS
4.2
Varity_R
0.13
gMVP
0.82
Mutation Taster
=17/83
disease causing

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: rs771749652; hg19: chr21-47552176; COSMIC: COSV99385115; COSMIC: COSV99385115; API