Genetic Variant COL12A1:p.Val2746Ala (chr6-75105234-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004370.6(COL12A1):c.8237T>C(p.Val2746Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,766 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2746I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0091 ( 12 hom., cov: 32)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.67

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008241266).

BP6

Variant 6-75105234-A-G is Benign according to our data. Variant chr6-75105234-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00911 (1387/152262) while in subpopulation NFE AF = 0.01 (682/68024). AF 95% confidence interval is 0.0094. There are 12 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	NM_004370.6	MANE Select	c.8237T>C	p.Val2746Ala	missense	Exon 54 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.8237T>C	p.Val2746Ala	missense	Exon 54 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.8216T>C	p.Val2739Ala	missense	Exon 53 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.8237T>C	p.Val2746Ala	missense	Exon 54 of 66	ENSP00000325146.8
COL12A1	ENST00000345356.10	TSL:1	c.4745T>C	p.Val1582Ala	missense	Exon 39 of 51	ENSP00000305147.9
COL12A1	ENST00000483888.6	TSL:5	c.8237T>C	p.Val2746Ala	missense	Exon 54 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1388

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00961

AC:

2395

AN:

249184

AF XY:

0.00956

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00778

GnomAD4 exome

AF:

0.0111

AC:

16155

AN:

1461504

Hom.:

110

Cov.:

AF XY:

0.0108

AC XY:

7850

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33464

American (AMR)

AF:

0.00166

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

831

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.00252

AC:

217

AN:

86232

European-Finnish (FIN)

AF:

0.0262

AC:

1398

AN:

53380

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0116

AC:

12886

AN:

1111800

Other (OTH)

AF:

0.0111

AC:

670

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

764

1528

2293

3057

3821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.00911

AC:

1387

AN:

152262

Hom.:

Cov.:

AF XY:

0.00970

AC XY:

722

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

41558

American (AMR)

AF:

0.00334

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

149

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0347

AC:

368

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

682

AN:

68024

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00996

Hom.:

Bravo

AF:

0.00681

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00214

AC:

ESP6500EA

AF:

0.0126

AC:

104

ExAC

AF:

0.00924

AC:

1116

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00758

EpiControl

AF:

0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL12A1: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0065

Eigen

Benign

0.052

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0082

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.47

PhyloP100

2.7

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.14

REVEL

Benign

0.26

Sift

Benign

0.82

Sift4G

Benign

0.95

Polyphen

0.87

Vest4

0.37

MVP

0.80

MPC

0.85

ClinPred

0.034

GERP RS

5.6

Varity_R

0.11

gMVP

0.47

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over