rs79830915

Variant names:

• chr6-75138453-C-T
• rs79830915
• NM_004370.6:c.5225G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-75138453-C-T
• chr6-75138453-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.5225G>A​(p.Arg1742His) variant causes a missense change. The variant allele was found at a frequency of 0.0036 in 1,613,066 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1742C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (85 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (66 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.73
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00811252).
• BP6: Variant 6-75138453-C-T is Benign according to our data. Variant chr6-75138453-C-T is described in ClinVar as Benign. ClinVar VariationId is 259337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

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.5225G>A	p.Arg1742His	missense	Exon 29 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.5225G>A	p.Arg1742His	missense	Exon 29 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.5225G>A	p.Arg1742His	missense	Exon 29 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.5225G>A	p.Arg1742His	missense	Exon 29 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.1733G>A	p.Arg578His	missense	Exon 14 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.5225G>A	p.Arg1742His	missense	Exon 29 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2845 AN: 152114 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00509 AC: 1263 AN: 247950 AF XY: 0.00387

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00203 AC: 2964 AN: 1460834 Hom.: 66 Cov.: 31 AF XY: 0.00176 AC XY: 1276 AN XY: 726648

African (AFR) AF: 0.0665 AC: 2223 AN: 33410

American (AMR) AF: 0.00527 AC: 235 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85932

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53392

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5764

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1111650

Other (OTH) AF: 0.00441 AC: 266 AN: 60362

GnomAD4 genome AF: 0.0187 AC: 2848 AN: 152232 Hom.: 85 Cov.: 32 AF XY: 0.0182 AC XY: 1353 AN XY: 74438

African (AFR) AF: 0.0641 AC: 2661 AN: 41526

American (AMR) AF: 0.00843 AC: 129 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68012

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.00585 Hom.: 44

Bravo AF: 0.0222

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0600 AC: 229

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00568 AC: 687

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

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	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.76
MPC		0.63
ClinPred		0.027	T
GERP RS		5.8
Varity_R		0.095
gMVP		0.66
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs79830915; hg19: chr6-75848169;