6-75132006-A-T

Variant names:

Variant summary

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

The NM_004370.6(COL12A1):c.5871T>A(p.Ala1957Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,613,972 control chromosomes in the GnomAD database, including 627,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1957A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 58810 hom., cov: 32)

Exomes 𝑓: 0.88 ( 568538 hom. )

Consequence

COL12A1
NM_004370.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.66

Publications

20 publications found

Variant links:

Genes affected

COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

COL12A1 Gene-Disease associations (from GenCC):

Bethlem myopathy 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Bethlem myopathy 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
Ullrich congenital muscular dystrophy 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL12A1 links:

Genome browser will be placed here

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=-0.93).

BP6

Variant 6-75132006-A-T is Benign according to our data. Variant chr6-75132006-A-T is described in ClinVar as Benign. ClinVar VariationId is 259341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.5871T>A	p.Ala1957Ala	synonymous_variant	Exon 35 of 66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL12A1	ENST00000322507.13 link	c.5871T>A	p.Ala1957Ala	synonymous_variant	Exon 35 of 66	1	NM_004370.6	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10 link	c.2379T>A	p.Ala793Ala	synonymous_variant	Exon 20 of 51	1		ENSP00000305147.9	Q99715-2
COL12A1	ENST00000483888.6 link	c.5871T>A	p.Ala1957Ala	synonymous_variant	Exon 35 of 65	5		ENSP00000421216.1	D6RGG3
COL12A1	ENST00000416123.6 link	c.5871T>A	p.Ala1957Ala	synonymous_variant	Exon 34 of 63	5		ENSP00000412864.2	Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

133622

AN:

152072

Hom.:

58758

Cov.:

show subpopulations

Gnomad AFR

AF:

0.869

Gnomad AMI

AF:

0.741

Gnomad AMR

AF:

0.900

Gnomad ASJ

AF:

0.896

Gnomad EAS

AF:

0.860

Gnomad SAS

AF:

0.865

Gnomad FIN

AF:

0.886

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.882

Gnomad OTH

AF:

0.875

GnomAD2 exomes

AF:

0.887

AC:

221131

AN:

249340

AF XY:

0.883

show subpopulations

Gnomad AFR exome

AF:

0.870

Gnomad AMR exome

AF:

0.931

Gnomad ASJ exome

AF:

0.896

Gnomad EAS exome

AF:

0.872

Gnomad FIN exome

AF:

0.890

Gnomad NFE exome

AF:

0.883

Gnomad OTH exome

AF:

0.885

GnomAD4 exome

AF:

0.882

AC:

1288908

AN:

1461782

Hom.:

568538

Cov.:

AF XY:

0.881

AC XY:

640323

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.877

AC:

29361

AN:

33476

American (AMR)

AF:

0.927

AC:

41455

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.898

AC:

23458

AN:

26134

East Asian (EAS)

AF:

0.856

AC:

33986

AN:

39694

South Asian (SAS)

AF:

0.862

AC:

74324

AN:

86254

European-Finnish (FIN)

AF:

0.892

AC:

47645

AN:

53416

Middle Eastern (MID)

AF:

0.871

AC:

5023

AN:

5768

European-Non Finnish (NFE)

AF:

0.882

AC:

980619

AN:

1111924

Other (OTH)

AF:

0.878

AC:

53037

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

8383

16766

25149

33532

41915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21362

42724

64086

85448

106810

<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:

0.879

AC:

133732

AN:

152190

Hom.:

58810

Cov.:

AF XY:

0.880

AC XY:

65438

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.869

AC:

36056

AN:

41500

American (AMR)

AF:

0.900

AC:

13771

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.896

AC:

3112

AN:

3472

East Asian (EAS)

AF:

0.861

AC:

4454

AN:

5174

South Asian (SAS)

AF:

0.864

AC:

4164

AN:

4818

European-Finnish (FIN)

AF:

0.886

AC:

9388

AN:

10594

Middle Eastern (MID)

AF:

0.898

AC:

264

AN:

294

European-Non Finnish (NFE)

AF:

0.882

AC:

60001

AN:

68018

Other (OTH)

AF:

0.876

AC:

1849

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

859

1719

2578

3438

4297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.882

Hom.:

14747

Bravo

AF:

0.881

Asia WGS

AF:

0.859

AC:

2989

AN:

3478

EpiCase

AF:

0.883

EpiControl

AF:

0.881

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bethlem myopathy 2

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ullrich congenital muscular dystrophy 2

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: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

-0.93

CADD

Benign

0.095

(source)

DANN

Benign

0.38

PhyloP100

-2.7

Mutation Taster

=79/21

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over