chr21-45981786-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_001848.3(COL6A1):c.-65C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

COL6A1
NM_001848.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0150

Publications

1 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:

LOC105372841 (HGNC:):

LOC105372841 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 21-45981786-C-G is Benign according to our data. Variant chr21-45981786-C-G is described in CliVar as Benign. Clinvar id is 340306.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000366 (54/147626) while in subpopulation NFE AF = 0.000687 (46/66912). AF 95% confidence interval is 0.000529. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.-65C>G		5_prime_UTR_variant	Exon 1 of 35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7
LOC105372841	XR_937803.3 link	n.*220C>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.-65C>G		5_prime_UTR_variant	Exon 1 of 35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.000366

AC:

AN:

147518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000754

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000994

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000687

Gnomad OTH

AF:

0.000494

GnomAD4 exome

AF:

0.000877

AC:

1009

AN:

1151016

Hom.:

Cov.:

AF XY:

0.000830

AC XY:

478

AN XY:

576014

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

25566

American (AMR)

AF:

0.000531

AC:

AN:

33882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22568

East Asian (EAS)

AF:

0.00

AC:

AN:

32424

South Asian (SAS)

AF:

0.00

AC:

AN:

71466

European-Finnish (FIN)

AF:

0.0000940

AC:

AN:

42552

Middle Eastern (MID)

AF:

0.000554

AC:

AN:

3608

European-Non Finnish (NFE)

AF:

0.00106

AC:

924

AN:

869752

Other (OTH)

AF:

0.00108

AC:

AN:

49198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

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

GnomAD4 genome

AF:

0.000366

AC:

AN:

147626

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

71912

show subpopulations

African (AFR)

AF:

0.0000752

AC:

AN:

39916

American (AMR)

AF:

0.000203

AC:

AN:

14754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

4866

South Asian (SAS)

AF:

0.00

AC:

AN:

4460

European-Finnish (FIN)

AF:

0.0000994

AC:

AN:

10062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000687

AC:

AN:

66912

Other (OTH)

AF:

0.000489

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000555

Hom.:

Bravo

AF:

0.000465

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.5

(source)

DANN

Benign

0.70

PhyloP100

0.015

PromoterAI

-0.096

Neutral

(source)

Mutation Taster

=300/0

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