Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004370.6(COL12A1):c.5508G>A(p.Thr1836Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,605,968 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 149 hom. )

Consequence

COL12A1
NM_004370.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.55

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.098).

BP6

Variant 6-75134742-C-T is Benign according to our data. Variant chr6-75134742-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.55 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00763 (1161/152230) while in subpopulation NFE AF = 0.0119 (810/68012). AF 95% confidence interval is 0.0112. There are 9 homozygotes in GnomAd4. There are 503 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 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.5508G>A	p.Thr1836Thr	synonymous	Exon 32 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.5508G>A	p.Thr1836Thr	synonymous	Exon 32 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.5487G>A	p.Thr1829Thr	synonymous	Exon 31 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.5508G>A	p.Thr1836Thr	synonymous	Exon 32 of 66	ENSP00000325146.8
COL12A1	ENST00000345356.10	TSL:1	c.2016G>A	p.Thr672Thr	synonymous	Exon 17 of 51	ENSP00000305147.9
COL12A1	ENST00000483888.6	TSL:5	c.5508G>A	p.Thr1836Thr	synonymous	Exon 32 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes

AF:

0.00763

AC:

1160

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00759

AC:

1887

AN:

248772

AF XY:

0.00802

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00349

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00697

GnomAD4 exome

AF:

0.0113

AC:

16453

AN:

1453738

Hom.:

149

Cov.:

AF XY:

0.0112

AC XY:

8106

AN XY:

723270

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

33406

American (AMR)

AF:

0.00338

AC:

151

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

660

AN:

25868

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39634

South Asian (SAS)

AF:

0.00692

AC:

588

AN:

84934

European-Finnish (FIN)

AF:

0.00234

AC:

124

AN:

52954

Middle Eastern (MID)

AF:

0.00471

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0128

AC:

14219

AN:

1106624

Other (OTH)

AF:

0.0105

AC:

632

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

802

1604

2406

3208

4010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.00763

AC:

1161

AN:

152230

Hom.:

Cov.:

AF XY:

0.00676

AC XY:

503

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

41530

American (AMR)

AF:

0.00275

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00642

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

810

AN:

68012

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

184

246

307

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:

0.0104

Hom.:

Bravo

AF:

0.00766

Asia WGS

AF:

0.00231

AC:

AN:

3478

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 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.36

(source)

DANN

Benign

0.38

PhyloP100

-3.5

Mutation Taster

=84/16

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.

rs77425231

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