Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004370.6(COL12A1):c.6922C>G(p.Pro2308Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000434 in 1,608,162 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 2 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.99

Publications

1 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09183112).

BP6

Variant 6-75123354-G-C is Benign according to our data. Variant chr6-75123354-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542491.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152256) while in subpopulation NFE AF = 0.000485 (33/68000). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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.6922C>G	p.Pro2308Ala	missense	Exon 43 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.6922C>G	p.Pro2308Ala	missense	Exon 43 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.6901C>G	p.Pro2301Ala	missense	Exon 42 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.6922C>G	p.Pro2308Ala	missense	Exon 43 of 66	ENSP00000325146.8
COL12A1	ENST00000345356.10	TSL:1	c.3430C>G	p.Pro1144Ala	missense	Exon 28 of 51	ENSP00000305147.9
COL12A1	ENST00000483888.6	TSL:5	c.6922C>G	p.Pro2308Ala	missense	Exon 43 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000197

AC:

AN:

238446

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000453

AC:

659

AN:

1455906

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

317

AN XY:

723538

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33366

American (AMR)

AF:

0.000136

AC:

AN:

44224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39484

South Asian (SAS)

AF:

0.000177

AC:

AN:

84888

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000553

AC:

613

AN:

1109058

Other (OTH)

AF:

0.000366

AC:

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000256

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41566

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000327

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.000489

AC:

ExAC

AF:

0.000224

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (2)

Bethlem myopathy 2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0079

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

5.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.11

Sift

Benign

0.083

Sift4G

Benign

0.086

Polyphen

0.54

Vest4

0.35

MVP

0.34

MPC

1.3

ClinPred

0.14

GERP RS

5.4

Varity_R

0.13

gMVP

0.36

Mutation Taster

=83/17

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs55997127

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over