6-75142113-A-C

Position:

chr6-75142113-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004370.6(COL12A1):c.4876T>G(p.Ser1626Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000685 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 5 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.22

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=0.008573294).

BP6

Variant 6-75142113-A-C is Benign according to our data. Variant chr6-75142113-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 542499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75142113-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00385 (586/152304) while in subpopulation AFR AF= 0.0137 (568/41568). AF 95% confidence interval is 0.0127. There are 8 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.4876T>G	p.Ser1626Ala	missense_variant	27/66	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.4876T>G	p.Ser1626Ala	missense_variant	27/66	1	NM_004370.6	ENSP00000325146	P4	Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00384

AC:

585

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000922

AC:

230

AN:

249406

Hom.:

AF XY:

0.000695

AC XY:

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000356

AC:

520

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.00385

AC:

586

AN:

152304

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0137

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000649

Hom.:

Bravo

AF:

0.00420

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00120

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2020

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;T;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T

MetaRNN

Benign

0.0086

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

.;M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

.;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.25

.;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.99, 1.0

.;D;D;.;.

Vest4

0.42

MVP

0.62

MPC

0.52

ClinPred

0.041

GERP RS

6.2

Varity_R

0.11

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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