chr21-46126476-T-TGGCCCGGCCCGGCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001849.4(COL6A2):​c.2423-18_2423-17insCGGCCCGGCCCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 152,210 control chromosomes in the GnomAD database, including 265 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.051 ( 265 hom., cov: 32)
Exomes 𝑓: 0.073 ( 4488 hom. )
Failed GnomAD Quality Control

Consequence

COL6A2
NM_001849.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.874

Publications

2 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: Benign. The variant received -10 ACMG points.

BP6
Variant 21-46126476-T-TGGCCCGGCCCGGCCC is Benign according to our data. Variant chr21-46126476-T-TGGCCCGGCCCGGCCC is described in ClinVar as [Likely_benign]. Clinvar id is 258324.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.2423-18_2423-17insCGGCCCGGCCCGGCC intron_variant Intron 26 of 27 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3
COL6A2NM_058174.3 linkc.2423-18_2423-17insCGGCCCGGCCCGGCC intron_variant Intron 26 of 27 NP_478054.2 P12110-2
COL6A2NM_058175.3 linkc.2423-18_2423-17insCGGCCCGGCCCGGCC intron_variant Intron 26 of 27 NP_478055.2 P12110-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.2423-27_2423-26insGGCCCGGCCCGGCCC intron_variant Intron 26 of 27 1 NM_001849.4 ENSP00000300527.4 P12110-1
COL6A2ENST00000397763.6 linkc.2423-27_2423-26insGGCCCGGCCCGGCCC intron_variant Intron 26 of 27 5 ENSP00000380870.1 P12110-2
COL6A2ENST00000409416.6 linkc.2423-27_2423-26insGGCCCGGCCCGGCCC intron_variant Intron 25 of 26 5 ENSP00000387115.1 P12110-3

Frequencies

GnomAD3 genomes
AF:
0.0511
AC:
7773
AN:
152092
Hom.:
267
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0151
Gnomad AMI
AF:
0.0670
Gnomad AMR
AF:
0.0420
Gnomad ASJ
AF:
0.0753
Gnomad EAS
AF:
0.0185
Gnomad SAS
AF:
0.0607
Gnomad FIN
AF:
0.0226
Gnomad MID
AF:
0.120
Gnomad NFE
AF:
0.0793
Gnomad OTH
AF:
0.0593
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0731
AC:
106489
AN:
1457208
Hom.:
4488
Cov.:
34
AF XY:
0.0730
AC XY:
52954
AN XY:
725056
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0137
AC:
457
AN:
33468
American (AMR)
AF:
0.0356
AC:
1591
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.0754
AC:
1968
AN:
26104
East Asian (EAS)
AF:
0.0211
AC:
836
AN:
39690
South Asian (SAS)
AF:
0.0618
AC:
5323
AN:
86168
European-Finnish (FIN)
AF:
0.0245
AC:
1293
AN:
52780
Middle Eastern (MID)
AF:
0.112
AC:
642
AN:
5754
European-Non Finnish (NFE)
AF:
0.0813
AC:
90136
AN:
1108310
Other (OTH)
AF:
0.0704
AC:
4243
AN:
60250
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.399
Heterozygous variant carriers
0
5017
10034
15052
20069
25086
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
3248
6496
9744
12992
16240
<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:
0.0510
AC:
7765
AN:
152210
Hom.:
265
Cov.:
32
AF XY:
0.0479
AC XY:
3567
AN XY:
74420
show subpopulations
African (AFR)
AF:
0.0151
AC:
628
AN:
41534
American (AMR)
AF:
0.0420
AC:
642
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.0753
AC:
261
AN:
3468
East Asian (EAS)
AF:
0.0186
AC:
96
AN:
5164
South Asian (SAS)
AF:
0.0605
AC:
292
AN:
4826
European-Finnish (FIN)
AF:
0.0226
AC:
240
AN:
10630
Middle Eastern (MID)
AF:
0.102
AC:
30
AN:
294
European-Non Finnish (NFE)
AF:
0.0793
AC:
5392
AN:
67970
Other (OTH)
AF:
0.0582
AC:
123
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
347
694
1042
1389
1736
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
100
200
300
400
500
<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:
0.0134
Hom.:
8

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 15, 2016
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.87
Mutation Taster
=100/0
polymorphism (auto)

Splicing

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

Publications

Other links and lift over

dbSNP: rs138363207; hg19: chr21-47546390; API