Genetic Variant COL12A1:p.Pro2802Arg (chr6-75102607-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004370.6(COL12A1):c.8405C>G(p.Pro2802Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2802L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.8405C>G	p.Pro2802Arg	missense_variant	Exon 56 of 66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 link	c.8405C>G	p.Pro2802Arg	missense_variant	Exon 56 of 66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396036

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29682

American (AMR)

AF:

0.00

AC:

AN:

34400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24132

East Asian (EAS)

AF:

0.00

AC:

AN:

35634

South Asian (SAS)

AF:

0.00

AC:

AN:

76360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081118

Other (OTH)

AF:

0.00

AC:

AN:

57202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

.;T;T;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D;D;T

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.58

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;.;M;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.5

N;.;N;N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.53

T;.;T;T;T;T

Sift4G

Benign

0.49

T;T;T;T;T;T

Polyphen

1.0

.;.;D;D;.;.

Vest4

0.41, 0.55, 0.53, 0.50, 0.46

MutPred

0.50

.;.;Gain of MoRF binding (P = 0.0137);.;.;Gain of MoRF binding (P = 0.0137);

MVP

0.74

MPC

1.4

ClinPred

0.98

GERP RS

5.0

Varity_R

0.26

gMVP

0.86

Mutation Taster

=71/29

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over