21-46003395-G-A

Variant names:

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.2469G>A(p.Thr823Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,600,540 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.69

Publications

2 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

COL6A1 links:

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=-0.77).

BP6

Variant 21-46003395-G-A is Benign according to our data. Variant chr21-46003395-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.68 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000899 (137/152308) while in subpopulation NFE AF = 0.00132 (90/68014). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.2469G>A	p.Thr823Thr	synonymous_variant	Exon 35 of 35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.2469G>A	p.Thr823Thr	synonymous_variant	Exon 35 of 35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000934

AC:

220

AN:

235586

AF XY:

0.000920

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.000960

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000339

Gnomad FIN exome

AF:

0.00215

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.00111

AC:

1606

AN:

1448232

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

754

AN XY:

721050

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33462

American (AMR)

AF:

0.000760

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.000126

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00263

AC:

106

AN:

40274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00124

AC:

1380

AN:

1111706

Other (OTH)

AF:

0.00121

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

150

200

250

<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:

0.000899

AC:

137

AN:

152308

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41578

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000561

Hom.:

Bravo

AF:

0.000661

EpiCase

AF:

0.00104

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jun 20, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 12, 2018

GeneDx

Significance:Likely 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 -

Bethlem myopathy 1A

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.50

(source)

DANN

Benign

0.58

PhyloP100

-3.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over