chr6-75115912-C-T

Variant names:

• chr6-75115912-C-T
• rs371624564
• NM_004370.6:c.7569G>A

Variant summary

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

The NM_004370.6(COL12A1):​c.7569G>A​(p.Met2523Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.7569G>A	p.Met2523Ile	missense	Exon 49 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.7569G>A	p.Met2523Ile	missense	Exon 49 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.7548G>A	p.Met2516Ile	missense	Exon 48 of 65	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.7569G>A	p.Met2523Ile	missense	Exon 49 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.4077G>A	p.Met1359Ile	missense	Exon 34 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.7569G>A	p.Met2523Ile	missense	Exon 49 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247640 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460544 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726538

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111456

Other (OTH) AF: 0.0000497 AC: 3 AN: 60304

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.011	D
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.35		Gain of methylation at K2522 (P = 0.0238)
MVP		0.63
MPC		0.55
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.86
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs371624564; hg19: chr6-75825628;