21-46000812-C-T

Variant names:

Variant summary

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

The NM_001848.3(COL6A1):c.1822+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00671 in 1,612,290 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 207 hom., cov: 36)

Exomes 𝑓: 0.0042 ( 222 hom. )

Consequence

COL6A1
NM_001848.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.133

Publications

11 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):

Bethlem myopathy 1A
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
collagen 6-related myopathy
Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 21-46000812-C-T is Benign according to our data. Variant chr21-46000812-C-T is described in ClinVar as Benign. ClinVar VariationId is 93833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.1822+45C>T		intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1822+45C>T	intron	N/A	ENSP00000355180.3	P12109
COL6A1	ENST00000866134.1		c.565-1715C>T	intron	N/A	ENSP00000536193.1
COL6A1	ENST00000466285.1	TSL:3	n.384C>T	non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4725

AN:

152170

Hom.:

208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.00942

AC:

2363

AN:

250872

AF XY:

0.00688

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00912

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00416

AC:

6069

AN:

1460002

Hom.:

222

Cov.:

AF XY:

0.00379

AC XY:

2754

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.107

AC:

3580

AN:

33446

American (AMR)

AF:

0.00968

AC:

433

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

278

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.000487

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53030

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000910

AC:

1011

AN:

1110670

Other (OTH)

AF:

0.0106

AC:

638

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

332

664

995

1327

1659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.0311

AC:

4742

AN:

152288

Hom.:

207

Cov.:

AF XY:

0.0285

AC XY:

2125

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.104

AC:

4333

AN:

41556

American (AMR)

AF:

0.0143

AC:

219

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68004

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

220

440

659

879

1099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.00439

Hom.:

5776

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.7

(source)

DANN

Benign

0.89

PhyloP100

-0.13

PromoterAI

-0.071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over