rs200315815

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_004370.6(COL12A1):c.1897G>T(p.Val633Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,507,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V633I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.285

Publications

2 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: Orphanet, Labcorp Genetics (formerly Invitae)
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=0.008966267).

BP6

Variant 6-75181206-C-A is Benign according to our data. Variant chr6-75181206-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475849.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00251 (215/85602) while in subpopulation AFR AF = 0.00871 (205/23532). AF 95% confidence interval is 0.00773. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL12A1	NM_004370.6	MANE Select	c.1897G>T	p.Val633Phe	missense	Exon 11 of 66	NP_004361.3
COL12A1	NM_001424113.1		c.1897G>T	p.Val633Phe	missense	Exon 11 of 66	NP_001411042.1
COL12A1	NM_001424114.1		c.1897G>T	p.Val633Phe	missense	Exon 11 of 65	NP_001411043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.1897G>T	p.Val633Phe	missense	Exon 11 of 66	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10	TSL:1	c.73+21514G>T		intron	N/A	ENSP00000305147.9	Q99715-2
COL12A1	ENST00000486533.1	TSL:1	n.1003G>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

215

AN:

85518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00143

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:

0.000963

GnomAD2 exomes

AF:

0.000447

AC:

AN:

196792

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.000841

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.000146

AC:

207

AN:

1421554

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

706022

show subpopulations

African (AFR)

AF:

0.00501

AC:

157

AN:

31322

American (AMR)

AF:

0.000694

AC:

AN:

37476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24786

East Asian (EAS)

AF:

0.00

AC:

AN:

39084

South Asian (SAS)

AF:

0.00

AC:

AN:

79896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.000189

AC:

AN:

5286

European-Non Finnish (NFE)

AF:

0.00000823

AC:

AN:

1093012

Other (OTH)

AF:

0.000239

AC:

AN:

58510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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

AF:

0.00251

AC:

215

AN:

85602

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

100

AN XY:

40718

show subpopulations

African (AFR)

AF:

0.00871

AC:

205

AN:

23532

American (AMR)

AF:

0.00143

AC:

AN:

6296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2198

East Asian (EAS)

AF:

0.00

AC:

AN:

2838

South Asian (SAS)

AF:

0.00

AC:

AN:

1690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42500

Other (OTH)

AF:

0.000947

AC:

AN:

1056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000598

Hom.:

Bravo

AF:

0.00178

ESP6500AA

AF:

0.00354

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000506

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.0

PhyloP100

0.28

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.44

Sift

Benign

0.040

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.19

MVP

0.58

MPC

0.22

ClinPred

0.011

GERP RS

4.8

Varity_R

0.088

gMVP

0.66

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over