rs78224483

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_StrongBP6_Strong

The NM_001848.3(COL6A1):c.1957-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0196 (AC=31,613) in the gnomAD database across 1,611,704 control chromosomes, including 389 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0254. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 40 hom., cov: 34)

Exomes 𝑓: 0.020 ( 349 hom. )

Consequence

COL6A1
NM_001848.3 splice_region, intron

Scores

Splicing: ADA: 0.00001802

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.836

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):

Bethlem myopathy 1A
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
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

new If you want to explore the variant's impact on the transcript NM_001848.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (12/12 total B/LB).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0254 vs gene BS1 threshold 0.015.

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 389.; Very high cumulative gnomAD AC = 31613 (any gene).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.1957-5C>T		splice_region intron	N/A	NP_001839.2	A0A384P5H7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1957-5C>T	splice_region intron	N/A	ENSP00000355180.3	P12109
COL6A1	ENST00000498614.5	TSL:1	n.191-5C>T	splice_region intron	N/A
COL6A1	ENST00000612273.2	TSL:5	c.82-5C>T	splice_region intron	N/A	ENSP00000483630.2	A0A087X0S5

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2615

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0254

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0264

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0171

AC:

4123

AN:

241412

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00340

Gnomad AMR exome

AF:

0.00654

Gnomad ASJ exome

AF:

0.0318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0294

Gnomad NFE exome

AF:

0.0258

Gnomad OTH exome

AF:

0.0172

GnomAD4 exome

AF:

0.0199

AC:

28998

AN:

1459444

Hom.:

349

Cov.:

AF XY:

0.0198

AC XY:

14367

AN XY:

726016

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33464

American (AMR)

AF:

0.00717

AC:

320

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0293

AC:

764

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00192

AC:

165

AN:

86018

European-Finnish (FIN)

AF:

0.0290

AC:

1508

AN:

51946

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0226

AC:

25135

AN:

1111560

Other (OTH)

AF:

0.0158

AC:

956

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1629

3259

4888

6518

8147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.0172

AC:

2615

AN:

152260

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1266

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00387

AC:

161

AN:

41550

American (AMR)

AF:

0.0127

AC:

195

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00249

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0309

AC:

328

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0264

AC:

1796

AN:

67992

Other (OTH)

AF:

0.0147

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

139

277

416

554

693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.0143

AC:

3787

AN:

264690

Hom.:

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0234

AC:

5803

AN:

248490

Hom.:

Local populations

ABraOM SABE-WGS-1171

AF:

0.0107

AC:

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.0000985

Denmark Genome

AF:

0.0133

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.0153

AC:

199

AN:

13002

show subpopulations

European American

AF:

0.0219

AC:

188

AN:

8598

African American

AF:

0.00250

AC:

AN:

4404

GenomeAsia100K

AF:

0.00231

AC:

AN:

3478

show subpopulations

Oceania

AF:

0.00

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.00142

AC:

AN:

702

Hom.:

South-East Asia

AF:

0.00

AC:

AN:

692

Hom.:

South Asia

AF:

0.00207

AC:

AN:

1448

Hom.:

Africa

AF:

0.00

AC:

AN:

208

Hom.:

America

AF:

0.00

AC:

AN:

Hom.:

West Eurasia

AF:

0.0175

AC:

AN:

228

Hom.:

Qatari Genome

AF:

0.00570

AC:

AN:

176

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000330

AC:

AN:

122553

Hom.:

Turkish Variome

AF:

0.0158

AC:

AN:

6060

Hom.:

UK10K

AF:

0.0193

AC:

146

AN:

7562

show subpopulations

TwinsUK

AF:

0.0190

AC:

AN:

3574

ALSPAC

AF:

0.0189

AC:

AN:

3854

Case/control cohorts

Cohort

Cases

Controls

BipEx

(Bipolar disorder (including schizoaffective))

624 / 28418AF: 0.0219579

680 / 28844AF: 0.0235751

SCHEMA

(Schizophrenia)

1518 / 97346AF: 0.0155939

3057 / 150920AF: 0.0202558

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (2)

Bethlem myopathy 1A (1)

Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.046

(source)

DANN

Benign

0.55

PhyloP100

-0.84

AlphaGenome AVI

Benign

0.0073

(source)

GPN-Star LLR

-1.8

(source)

GPN-Star score

1.8

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.090

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over