rs35710072

Positions:

• chr6-75113656-T-C

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.7786A>G​(p.Ile2596Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,608,682 control chromosomes in the GnomAD database, including 1,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (607 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (573 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.48

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=0.002072066).
• BP6: Variant 6-75113656-T-C is Benign according to our data. Variant chr6-75113656-T-C is described in ClinVar as [Benign]. Clinvar id is 259347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75113656-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.7786A>G	p.Ile2596Val	missense_variant	50/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.7786A>G	p.Ile2596Val	missense_variant	50/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 7468 AN: 151680 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000885

Gnomad OTH AF: 0.0322

GnomAD3 exomes AF: 0.0128 AC: 3187 AN: 248646 Hom.: 249 AF XY: 0.00954 AC XY: 1287 AN XY: 134964

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.00897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00596

GnomAD4 exome AF: 0.00529 AC: 7711 AN: 1456884 Hom.: 573 Cov.: 30 AF XY: 0.00455 AC XY: 3300 AN XY: 724862

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000677

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0494 AC: 7502 AN: 151798 Hom.: 607 Cov.: 32 AF XY: 0.0476 AC XY: 3532 AN XY: 74224

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000885

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.00939 Hom.: 163

Bravo AF: 0.0560

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.171 AC: 620

ESP6500EA AF: 0.00110 AC: 9

ExAC AF: 0.0155 AC: 1872

Asia WGS AF: 0.0120 AC: 42 AN: 3476

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	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	0.012	P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.68	N;.;N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.15	T;.;T;T;T;T;T
Sift4G	Benign	0.20	T;D;D;D;D;D;T
Polyphen		0.50, 0.88	.;.;P;P;.;.;.
Vest4		0.21, 0.16, 0.25, 0.27
MPC		0.43
ClinPred		0.023	T
GERP RS		4.6
Varity_R		0.072
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs35710072; hg19: chr6-75823372;