6-75165776-C-T

Position:

chr6-75165776-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_004370.6(COL12A1):c.2714G>A(p.Arg905His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,610,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.90

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.14537913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.2714G>A	p.Arg905His	missense_variant	14/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.2714G>A	p.Arg905His	missense_variant	14/66	1	NM_004370.6	ENSP00000325146	P4	Q99715-1
COL12A1	ENST00000345356.10 linkuse as main transcript	c.74-13294G>A		intron_variant		1		ENSP00000305147		Q99715-2
COL12A1	ENST00000483888.6 linkuse as main transcript	c.2714G>A	p.Arg905His	missense_variant	14/65	5		ENSP00000421216	A1
COL12A1	ENST00000416123.6 linkuse as main transcript	c.2714G>A	p.Arg905His	missense_variant	13/63	5		ENSP00000412864		Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000138

AC:

AN:

246836

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

133898

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000280

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1458244

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

725148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000584

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2024	Has not been previously published as pathogenic or benign in association with COL12A1-related myopathies to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28407358, 34011629, 31785789, 35982159, 35982160, 25363768) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 19, 2024	- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.46

MVP

0.57

MPC

0.63

ClinPred

0.52

GERP RS

5.3

Varity_R

0.10

gMVP

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over