6-75115791-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001424113.1(COL12A1):c.7690C>T(p.Pro2564Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,609,286 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

COL12A1
NM_001424113.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 9.52

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037420213).

BP6

Variant 6-75115791-G-A is Benign according to our data. Variant chr6-75115791-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542500.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000394 (60/152240) while in subpopulation AFR AF = 0.00132 (55/41546). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424113.1. 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.7690C>T	p.Pro2564Ser	missense	Exon 49 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.7690C>T	p.Pro2564Ser	missense	Exon 49 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.7669C>T	p.Pro2557Ser	missense	Exon 48 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.7690C>T	p.Pro2564Ser	missense	Exon 49 of 66	ENSP00000325146.8
COL12A1	ENST00000345356.10	TSL:1	c.4198C>T	p.Pro1400Ser	missense	Exon 34 of 51	ENSP00000305147.9
COL12A1	ENST00000483888.6	TSL:5	c.7690C>T	p.Pro2564Ser	missense	Exon 49 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000115

AC:

AN:

244402

AF XY:

0.0000755

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000343

AC:

AN:

1457046

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

724630

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

33064

American (AMR)

AF:

0.0000457

AC:

AN:

43770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000705

AC:

AN:

85068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110378

Other (OTH)

AF:

0.0000665

AC:

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000394

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41546

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000131

Hom.:

Bravo

AF:

0.000491

ESP6500AA

AF:

0.00179

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000190

AC:

Asia WGS

AF:

0.000289

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 (2)

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)

Bethlem myopathy;C4551860:Ullrich congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.047

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.8

PhyloP100

9.5

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.50

Sift

Benign

0.10

Sift4G

Benign

0.27

Polyphen

1.0

Vest4

0.75

MVP

0.49

MPC

1.4

ClinPred

0.14

GERP RS

4.8

Varity_R

0.49

gMVP

0.62

Mutation Taster

=39/61

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over