chr2-237379157-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004369.4(COL6A3):​c.1976G>A​(p.Arg659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,614,136 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R659C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 155 hom., cov: 33)
Exomes 𝑓: 0.0024 ( 136 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

4
9
5

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.64

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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005715698).
BP6
Variant 2-237379157-C-T is Benign according to our data. Variant chr2-237379157-C-T is described in ClinVar as [Benign]. Clinvar id is 94914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A3NM_004369.4 linkc.1976G>A p.Arg659His missense_variant Exon 6 of 44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkc.1976G>A p.Arg659His missense_variant Exon 6 of 44 1 NM_004369.4 ENSP00000295550.4 P12111-1

Frequencies

GnomAD3 genomes
AF:
0.0247
AC:
3754
AN:
152130
Hom.:
154
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0860
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00870
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.0172
GnomAD2 exomes
AF:
0.00629
AC:
1574
AN:
250204
AF XY:
0.00461
show subpopulations
Gnomad AFR exome
AF:
0.0862
Gnomad AMR exome
AF:
0.00393
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000124
Gnomad OTH exome
AF:
0.00294
GnomAD4 exome
AF:
0.00241
AC:
3523
AN:
1461888
Hom.:
136
Cov.:
33
AF XY:
0.00214
AC XY:
1558
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.0866
AC:
2898
AN:
33478
American (AMR)
AF:
0.00458
AC:
205
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000220
AC:
19
AN:
86258
European-Finnish (FIN)
AF:
0.000281
AC:
15
AN:
53420
Middle Eastern (MID)
AF:
0.00260
AC:
15
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000755
AC:
84
AN:
1112010
Other (OTH)
AF:
0.00475
AC:
287
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
203
406
608
811
1014
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
90
180
270
360
450
<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:
0.0247
AC:
3764
AN:
152248
Hom.:
155
Cov.:
33
AF XY:
0.0238
AC XY:
1771
AN XY:
74442
show subpopulations
African (AFR)
AF:
0.0860
AC:
3573
AN:
41530
American (AMR)
AF:
0.00869
AC:
133
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5192
South Asian (SAS)
AF:
0.000830
AC:
4
AN:
4820
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000206
AC:
14
AN:
68022
Other (OTH)
AF:
0.0171
AC:
36
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
179
359
538
718
897
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
36
72
108
144
180
<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:
0.0100
Hom.:
125
Bravo
AF:
0.0278
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.0794
AC:
350
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00764
AC:
927
Asia WGS
AF:
0.00346
AC:
12
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Nov 05, 2012
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 13, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2
Nov 14, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Bethlem myopathy 1A Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Collagen 6-related myopathy Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.58
.;D;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
D;D;.;D;D
MetaRNN
Benign
0.0057
T;T;T;T;T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Pathogenic
3.5
.;M;.;.;.
PhyloP100
2.6
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0020
D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.74
MVP
0.97
MPC
0.72
ClinPred
0.058
T
GERP RS
5.5
Varity_R
0.68
gMVP
0.59
Mutation Taster
=90/10
polymorphism (auto)

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: rs36092870; hg19: chr2-238287800; API