rs77094372

Variant names:

• chr6-75123971-C-T
• rs77094372
• NM_004370.6:c.6848G>A
• COL12A1 p.Gly2283Glu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.6848G>A​(p.Gly2283Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00211 in 1,613,300 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (26 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.18
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063426495).
• BP6: Variant 6-75123971-C-T is Benign according to our data. Variant chr6-75123971-C-T is described in ClinVar as Benign. ClinVar VariationId is 475891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1630/152250) while in subpopulation AFR AF = 0.0367 (1524/41542). AF 95% confidence interval is 0.0352. There are 25 homozygotes in GnomAd4. There are 776 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

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.6848G>A	p.Gly2283Glu	missense	Exon 42 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.6848G>A	p.Gly2283Glu	missense	Exon 42 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.6827G>A	p.Gly2276Glu	missense	Exon 41 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.6848G>A	p.Gly2283Glu	missense	Exon 42 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.3356G>A	p.Gly1119Glu	missense	Exon 27 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.6848G>A	p.Gly2283Glu	missense	Exon 42 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 152132 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00261 AC: 650 AN: 248698 AF XY: 0.00202

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00121 AC: 1774 AN: 1461050 Hom.: 26 Cov.: 31 AF XY: 0.00109 AC XY: 793 AN XY: 726694

African (AFR) AF: 0.0369 AC: 1235 AN: 33442

American (AMR) AF: 0.00213 AC: 95 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5760

European-Non Finnish (NFE) AF: 0.000198 AC: 220 AN: 1111422

Other (OTH) AF: 0.00306 AC: 185 AN: 60362

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152250 Hom.: 25 Cov.: 32 AF XY: 0.0104 AC XY: 776 AN XY: 74444

African (AFR) AF: 0.0367 AC: 1524 AN: 41542

American (AMR) AF: 0.00438 AC: 67 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68014

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00359 Hom.: 27

Bravo AF: 0.0116

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.000491

EpiControl AF: 0.000712

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.16
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.24
gMVP		0.79
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77094372;

hg19: chr6-75833687;