rs200646131

Variant names:

• chr6-75102607-G-A
• rs200646131
• NM_004370.6:c.8405C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-75102607-G-A
• chr6-75102607-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):​c.8405C>T​(p.Pro2802Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,548,162 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. P2802R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.57
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022657454).
• BP6: Variant 6-75102607-G-A is Benign according to our data. Variant chr6-75102607-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475900.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00116 (176/152138) while in subpopulation AFR AF = 0.00407 (169/41488). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.8405C>T	p.Pro2802Leu	missense	Exon 56 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.8405C>T	p.Pro2802Leu	missense	Exon 56 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.8384C>T	p.Pro2795Leu	missense	Exon 55 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.8405C>T	p.Pro2802Leu	missense	Exon 56 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.4913C>T	p.Pro1638Leu	missense	Exon 41 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.8405C>T	p.Pro2802Leu	missense	Exon 56 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000248 AC: 51 AN: 205448 AF XY: 0.000230

Gnomad AFR exome AF: 0.00319

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000408

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 145 AN: 1396024 Hom.: 0 Cov.: 30 AF XY: 0.0000821 AC XY: 57 AN XY: 694104

African (AFR) AF: 0.00286 AC: 85 AN: 29678

American (AMR) AF: 0.000349 AC: 12 AN: 34400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24132

East Asian (EAS) AF: 0.00 AC: 0 AN: 35634

South Asian (SAS) AF: 0.0000786 AC: 6 AN: 76360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.0000231 AC: 25 AN: 1081112

Other (OTH) AF: 0.000297 AC: 17 AN: 57200

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74378

African (AFR) AF: 0.00407 AC: 169 AN: 41488

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000841 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00300 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000306 AC: 37

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	COL12A1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.023	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.54
Sift	Benign	0.15	T
Sift4G	Benign	0.071	T
Polyphen		1.0	D
Vest4		0.38
MVP		0.85
MPC		1.3
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.82
Mutation Taster		=68/32	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: rs200646131; hg19: chr6-75812323;