chr21-46002371-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001848.3(COL6A1):​c.2220G>A​(p.Pro740Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,594,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P740P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 34)
Exomes 𝑓: 0.00092 ( 5 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.96

Publications

0 publications found
Variant links:
Genes affected
COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]
COL6A1 Gene-Disease associations (from GenCC):
  • collagen 6-related myopathy
    Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
  • Bethlem myopathy 1A
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
  • Ullrich congenital muscular dystrophy 1A
    Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 21-46002371-G-A is Benign according to our data. Variant chr21-46002371-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.96 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00176 (268/152340) while in subpopulation AFR AF = 0.00325 (135/41578). AF 95% confidence interval is 0.0028. There are 2 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A1NM_001848.3 linkc.2220G>A p.Pro740Pro synonymous_variant Exon 32 of 35 ENST00000361866.8 NP_001839.2 P12109A0A384P5H7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A1ENST00000361866.8 linkc.2220G>A p.Pro740Pro synonymous_variant Exon 32 of 35 1 NM_001848.3 ENSP00000355180.3 P12109

Frequencies

GnomAD3 genomes
AF:
0.00178
AC:
271
AN:
152222
Hom.:
2
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00328
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.0101
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.000926
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.00159
AC:
334
AN:
210698
AF XY:
0.00158
show subpopulations
Gnomad AFR exome
AF:
0.00270
Gnomad AMR exome
AF:
0.00228
Gnomad ASJ exome
AF:
0.00880
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00122
Gnomad OTH exome
AF:
0.00297
GnomAD4 exome
AF:
0.000922
AC:
1329
AN:
1441730
Hom.:
5
Cov.:
35
AF XY:
0.000946
AC XY:
677
AN XY:
715824
show subpopulations
African (AFR)
AF:
0.00393
AC:
130
AN:
33098
American (AMR)
AF:
0.00208
AC:
86
AN:
41276
Ashkenazi Jewish (ASJ)
AF:
0.00917
AC:
236
AN:
25750
East Asian (EAS)
AF:
0.0000517
AC:
2
AN:
38672
South Asian (SAS)
AF:
0.000546
AC:
46
AN:
84212
European-Finnish (FIN)
AF:
0.0000395
AC:
2
AN:
50586
Middle Eastern (MID)
AF:
0.00644
AC:
37
AN:
5748
European-Non Finnish (NFE)
AF:
0.000633
AC:
698
AN:
1102784
Other (OTH)
AF:
0.00154
AC:
92
AN:
59604
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
102
204
306
408
510
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
24
48
72
96
120
<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:
0.00176
AC:
268
AN:
152340
Hom.:
2
Cov.:
34
AF XY:
0.00142
AC XY:
106
AN XY:
74488
show subpopulations
African (AFR)
AF:
0.00325
AC:
135
AN:
41578
American (AMR)
AF:
0.00163
AC:
25
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.0101
AC:
35
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.0238
AC:
7
AN:
294
European-Non Finnish (NFE)
AF:
0.000926
AC:
63
AN:
68032
Other (OTH)
AF:
0.000946
AC:
2
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
15
30
44
59
74
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome 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
Alfa
AF:
0.00177
Hom.:
0
Bravo
AF:
0.00202
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Apr 20, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

COL6A1: BP4, BP7 -

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

- -

not specified Benign:1
May 04, 2015
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Collagen 6-related myopathy Benign:1
Jan 12, 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. -

Bethlem myopathy 1A Benign:1
Jan 23, 2025
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
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.33
DANN
Benign
0.50
PhyloP100
-5.0
Mutation Taster
=100/0
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: rs138976133; hg19: chr21-47422285; COSMIC: COSV100720350; COSMIC: COSV100720350; API