Genetic Variant COL12A1:p.Tyr632Tyr (chr6-75181207-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_004370.6(COL12A1):c.1896C>T(p.Tyr632Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,497,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

COL12A1
NM_004370.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00

Publications

0 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 6-75181207-G-A is Benign according to our data. Variant chr6-75181207-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00148 (110/74240) while in subpopulation AFR AF = 0.00436 (92/21110). AF 95% confidence interval is 0.00364. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1896C>T	p.Tyr632Tyr	synonymous	Exon 11 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.1896C>T	p.Tyr632Tyr	synonymous	Exon 11 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.1896C>T	p.Tyr632Tyr	synonymous	Exon 11 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.1896C>T	p.Tyr632Tyr	synonymous	Exon 11 of 66	ENSP00000325146.8
COL12A1	ENST00000486533.1	TSL:1	n.1002C>T		non_coding_transcript_exon	Exon 4 of 5
COL12A1	ENST00000345356.10	TSL:1	c.73+21513C>T		intron	N/A	ENSP00000305147.9

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

109

AN:

74140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000753

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000821

Gnomad OTH

AF:

0.00231

GnomAD2 exomes

AF:

0.000250

AC:

AN:

191852

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.00233

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:

0.0000548

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

AF:

0.000165

AC:

235

AN:

1423546

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

103

AN XY:

707262

show subpopulations

African (AFR)

AF:

0.00270

AC:

AN:

31426

American (AMR)

AF:

0.000212

AC:

AN:

37762

Ashkenazi Jewish (ASJ)

AF:

0.0000403

AC:

AN:

24844

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39318

South Asian (SAS)

AF:

0.000211

AC:

AN:

80504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52274

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5328

European-Non Finnish (NFE)

AF:

0.0000942

AC:

103

AN:

1093464

Other (OTH)

AF:

0.000324

AC:

AN:

58626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.00148

AC:

110

AN:

74240

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

AN XY:

35276

show subpopulations

African (AFR)

AF:

0.00436

AC:

AN:

21110

American (AMR)

AF:

0.00227

AC:

AN:

5296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1914

East Asian (EAS)

AF:

0.00

AC:

AN:

2426

South Asian (SAS)

AF:

0.000749

AC:

AN:

1336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.0000821

AC:

AN:

36530

Other (OTH)

AF:

0.00228

AC:

AN:

878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

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:

0.000348

Hom.:

Bravo

AF:

0.000820

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL12A1: BP4, BP7

Oct 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.83

(source)

DANN

Benign

0.13

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

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