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 (★★). 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

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 where missense usually causes diseases, COL12A1
• 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	UniProt
COL12A1	NM_004370.6	c.5225G>A	p.Arg1742His	missense_variant	29/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5225G>A	p.Arg1742His	missense_variant	29/66	1	NM_004370.6	P4

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

Invitae

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
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
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;