chr6-75189584-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004370.6(COL12A1):c.626A>C(p.Lys209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,054 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 127 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.630

Publications

6 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=0.0027424395).

BP6

Variant 6-75189584-T-G is Benign according to our data. Variant chr6-75189584-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

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.626A>C	p.Lys209Thr	missense	Exon 6 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.626A>C	p.Lys209Thr	missense	Exon 6 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.626A>C	p.Lys209Thr	missense	Exon 6 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.626A>C	p.Lys209Thr	missense	Exon 6 of 66	ENSP00000325146.8
COL12A1	ENST00000345356.10	TSL:1	c.73+13136A>C		intron	N/A	ENSP00000305147.9
COL12A1	ENST00000483888.6	TSL:5	c.626A>C	p.Lys209Thr	missense	Exon 6 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3414

AN:

152078

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0781

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00879

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00565

AC:

1395

AN:

246950

AF XY:

0.00449

show subpopulations

Gnomad AFR exome

AF:

0.0795

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.00268

GnomAD4 exome

AF:

0.00230

AC:

3361

AN:

1460858

Hom.:

127

Cov.:

AF XY:

0.00198

AC XY:

1439

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.0817

AC:

2733

AN:

33444

American (AMR)

AF:

0.00450

AC:

201

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.000220

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1111472

Other (OTH)

AF:

0.00547

AC:

330

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.0225

AC:

3421

AN:

152196

Hom.:

112

Cov.:

AF XY:

0.0212

AC XY:

1580

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0780

AC:

3241

AN:

41542

American (AMR)

AF:

0.00878

AC:

134

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

67948

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

166

332

498

664

830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00874

Hom.:

Bravo

AF:

0.0259

ESP6500AA

AF:

0.0767

AC:

278

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00680

AC:

821

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.097

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.17

PhyloP100

0.63

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.44

REVEL

Benign

0.15

Sift

Benign

0.21

Sift4G

Benign

0.84

Polyphen

0.010

Vest4

0.30

MVP

0.42

MPC

0.17

ClinPred

0.0031

GERP RS

0.43

Varity_R

0.048

gMVP

0.71

Mutation Taster

=98/2

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

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