6-75132038-G-T

Variant names:

Variant summary

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

The NM_004370.6(COL12A1):c.5839C>A(p.Pro1947Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1947L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.62

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039941818).

BP6

Variant 6-75132038-G-T is Benign according to our data. Variant chr6-75132038-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475878.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000236 (36/152356) while in subpopulation AFR AF = 0.000361 (15/41594). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL12A1	ENST00000322507.13 link	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10 link	c.2347C>A	p.Pro783Thr	missense_variant	Exon 20 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6 link	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 35 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6 link	c.5839C>A	p.Pro1947Thr	missense_variant	Exon 34 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000169

AC:

AN:

249256

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000189

AC:

276

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000186

AC:

207

AN:

1111954

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000236

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41594

American (AMR)

AF:

0.000261

AC:

AN:

15304

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:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68038

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000137

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.000496

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000190

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Uncertain:2Benign:1

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2023

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Mar 03, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 475878; Landrum et al., 2016) -

not specified

Benign:1

Dec 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL12A1 c.5839C>A (p.Pro1947Thr) results in a non-conservative amino acid change located in the Fibronectin type III repeat domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 1614188 control chromosomes in the gnomAD database (v4.1 dataset), including 1 homozygote. To our knowledge, no occurrence of c.5839C>A in individuals affected with Ullrich congenital muscular dystrophy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 475878). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.093

DEOGEN2

Benign

0.012

T;T;.;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Benign

0.0053

MetaRNN

Benign

0.040

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.070

.;N;.;N;.

PhyloP100

2.6

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.87

.;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

.;T;T;T;T

Sift4G

Benign

0.58

T;T;T;T;T

Polyphen

0.021, 0.0040

.;B;B;.;.

Vest4

0.12

MVP

0.23

MPC

0.21

ClinPred

0.030

GERP RS

6.2

Varity_R

0.088

gMVP

0.52

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over