Genetic Variant COL6A2:p.Pro221Pro (chr21-46112526-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001849.4(COL6A2):c.663C>T(p.Pro221Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,607,688 control chromosomes in the GnomAD database, including 6,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 716 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5389 hom. )

Consequence

COL6A2
NM_001849.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -4.81

Publications

8 publications found

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, SD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1B
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
Bethlem myopathy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD 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
myosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL6A2 links:

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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=-0.61).

BP6

Variant 21-46112526-C-T is Benign according to our data. Variant chr21-46112526-C-T is described in ClinVar as Benign. ClinVar VariationId is 93955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A2	NM_001849.4	MANE Select	c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	NP_001840.3
COL6A2	NM_058174.3	MANE Plus Clinical	c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	NP_478054.2	P12110-2
COL6A2	NM_058175.3		c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	NP_478055.2	P12110-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	ENSP00000380870.1	P12110-2
COL6A2	ENST00000857098.1		c.663C>T	p.Pro221Pro	synonymous	Exon 3 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes

AF:

0.0968

AC:

14394

AN:

148678

Hom.:

715

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.0816

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0538

Gnomad FIN

AF:

0.0934

Gnomad MID

AF:

0.0709

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.0854

AC:

20844

AN:

244032

AF XY:

0.0835

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.0776

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0924

Gnomad NFE exome

AF:

0.0827

Gnomad OTH exome

AF:

0.0810

GnomAD4 exome

AF:

0.0839

AC:

122364

AN:

1458894

Hom.:

5389

Cov.:

AF XY:

0.0833

AC XY:

60487

AN XY:

725808

show subpopulations

African (AFR)

AF:

0.127

AC:

4249

AN:

33470

American (AMR)

AF:

0.0770

AC:

3434

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0796

AC:

2077

AN:

26104

East Asian (EAS)

AF:

0.102

AC:

4031

AN:

39454

South Asian (SAS)

AF:

0.0607

AC:

5231

AN:

86210

European-Finnish (FIN)

AF:

0.0951

AC:

4901

AN:

51522

Middle Eastern (MID)

AF:

0.0831

AC:

479

AN:

5766

European-Non Finnish (NFE)

AF:

0.0835

AC:

92844

AN:

1111432

Other (OTH)

AF:

0.0848

AC:

5118

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7510

15020

22531

30041

37551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3506

7012

10518

14024

17530

<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:

0.0969

AC:

14419

AN:

148794

Hom.:

716

Cov.:

AF XY:

0.0965

AC XY:

7006

AN XY:

72628

show subpopulations

African (AFR)

AF:

0.126

AC:

5067

AN:

40186

American (AMR)

AF:

0.0937

AC:

1406

AN:

15004

Ashkenazi Jewish (ASJ)

AF:

0.0816

AC:

278

AN:

3408

East Asian (EAS)

AF:

0.127

AC:

630

AN:

4962

South Asian (SAS)

AF:

0.0532

AC:

246

AN:

4626

European-Finnish (FIN)

AF:

0.0934

AC:

981

AN:

10506

Middle Eastern (MID)

AF:

0.0725

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0819

AC:

5476

AN:

66886

Other (OTH)

AF:

0.105

AC:

213

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

648

1296

1945

2593

3241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.0853

Hom.:

426

Bravo

AF:

0.0982

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

EpiCase

AF:

0.0796

EpiControl

AF:

0.0790

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)

Myosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.9

(source)

DANN

Benign

0.86

PhyloP100

-4.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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