rs35523808

Positions:

chr6-75125255-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004370.6(COL12A1):c.6479A>T(p.Glu2160Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,607,394 control chromosomes in the GnomAD database, including 1,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 135 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1729 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.36

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 Benign. Variant got -19 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=0.003599733).

BP6

Variant 6-75125255-T-A is Benign according to our data. Variant chr6-75125255-T-A is described in ClinVar as [Benign]. Clinvar id is 259344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75125255-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.6479A>T	p.Glu2160Val	missense_variant	40/66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.6479A>T	p.Glu2160Val	missense_variant	40/66	1	NM_004370.6	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10 linkuse as main transcript	c.2987A>T	p.Glu996Val	missense_variant	25/51	1		ENSP00000305147.9	Q99715-2
COL12A1	ENST00000483888.6 linkuse as main transcript	c.6479A>T	p.Glu2160Val	missense_variant	40/65	5		ENSP00000421216.1	D6RGG3
COL12A1	ENST00000416123.6 linkuse as main transcript	c.6479A>T	p.Glu2160Val	missense_variant	39/63	5		ENSP00000412864.2	Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5235

AN:

152082

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0242

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0574

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0537

Gnomad OTH

AF:

0.0340

GnomAD3 exomes

AF:

0.0343

AC:

8376

AN:

243970

Hom.:

199

AF XY:

0.0348

AC XY:

4599

AN XY:

132278

show subpopulations

Gnomad AFR exome

AF:

0.00711

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.00691

Gnomad FIN exome

AF:

0.0563

Gnomad NFE exome

AF:

0.0511

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0446

AC:

64952

AN:

1455194

Hom.:

1729

Cov.:

AF XY:

0.0438

AC XY:

31702

AN XY:

723574

show subpopulations

Gnomad4 AFR exome

AF:

0.00704

Gnomad4 AMR exome

AF:

0.0204

Gnomad4 ASJ exome

AF:

0.0299

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00701

Gnomad4 FIN exome

AF:

0.0574

Gnomad4 NFE exome

AF:

0.0513

Gnomad4 OTH exome

AF:

0.0393

GnomAD4 genome

AF:

0.0344

AC:

5233

AN:

152200

Hom.:

135

Cov.:

AF XY:

0.0337

AC XY:

2511

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00845

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0574

Gnomad4 NFE

AF:

0.0537

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0471

Hom.:

140

Bravo

AF:

0.0312

TwinsUK

AF:

0.0494

AC:

183

ALSPAC

AF:

0.0439

AC:

169

ESP6500AA

AF:

0.00924

AC:

ESP6500EA

AF:

0.0474

AC:

390

ExAC

AF:

0.0334

AC:

4037

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0503

EpiControl

AF:

0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

T;T;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

.;L;.;L;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.0

.;D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.54

MPC

1.5

ClinPred

0.0069

GERP RS

5.2

Varity_R

0.63

gMVP

0.70

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