rs79830915

Positions:

• chr6-75138453-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.
• 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 id is 259337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75138453-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5225G>A	p.Arg1742His	missense_variant	29/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5225G>A	p.Arg1742His	missense_variant	29/66	1	NM_004370.6	ENSP00000325146.8

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

GnomAD3 exomes AF: 0.00509 AC: 1263 AN: 247950 Hom.: 30 AF XY: 0.00387 AC XY: 521 AN XY: 134468

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 SAS exome AF: 0.000232

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

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.00527

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00441

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

Gnomad4 AFR AF: 0.0641

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00341 Hom.: 21

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.9	.;M;.;M;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	.;N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	.;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	.;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs79830915; hg19: chr6-75848169;