chr21-45990401-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_001848.3(COL6A1):c.981C>T(p.Ile327Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,371,302 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.29

Publications

3 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 21-45990401-C-T is Benign according to our data. Variant chr21-45990401-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000674 (74/109736) while in subpopulation AMR AF = 0.00134 (13/9678). AF 95% confidence interval is 0.000795. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.981C>T	p.Ile327Ile	synonymous_variant	Exon 13 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.981C>T	p.Ile327Ile	synonymous_variant	Exon 13 of 35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.000666

AC:

AN:

109616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.000643

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000863

Gnomad OTH

AF:

0.000683

GnomAD2 exomes

AF:

0.000730

AC:

162

AN:

221830

AF XY:

0.000709

show subpopulations

Gnomad AFR exome

AF:

0.000576

Gnomad AMR exome

AF:

0.000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000287

Gnomad FIN exome

AF:

0.000476

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.00124

AC:

1559

AN:

1261566

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

748

AN XY:

625088

show subpopulations

African (AFR)

AF:

0.000351

AC:

AN:

28484

American (AMR)

AF:

0.000938

AC:

AN:

38390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19182

East Asian (EAS)

AF:

0.0000932

AC:

AN:

21464

South Asian (SAS)

AF:

0.0000250

AC:

AN:

79976

European-Finnish (FIN)

AF:

0.000653

AC:

AN:

35198

Middle Eastern (MID)

AF:

0.000427

AC:

AN:

4688

European-Non Finnish (NFE)

AF:

0.00144

AC:

1421

AN:

986894

Other (OTH)

AF:

0.00133

AC:

AN:

47290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

198

264

330

<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:

0.000674

AC:

AN:

109736

Hom.:

Cov.:

AF XY:

0.000478

AC XY:

AN XY:

52354

show subpopulations

African (AFR)

AF:

0.000310

AC:

AN:

32288

American (AMR)

AF:

0.00134

AC:

AN:

9678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2542

East Asian (EAS)

AF:

0.00

AC:

AN:

2988

South Asian (SAS)

AF:

0.000377

AC:

AN:

2656

European-Finnish (FIN)

AF:

0.000643

AC:

AN:

6222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.000863

AC:

AN:

51004

Other (OTH)

AF:

0.00135

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.000886

Hom.:

Bravo

AF:

0.000616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL6A1: BP4, BP7 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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. -

Bethlem myopathy 1A

Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.52

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

-1.3

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