rs35523808

chr6-75125255-T-A

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.6479A>T(p.Glu2160Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,607,394 control chromosomes in the GnomAD database, including 1,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (135 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1729 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.36

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=0.003599733).
• BP6: Variant 6-75125255-T-A is Benign according to our data. Variant chr6-75125255-T-A is described in ClinVar as [Benign]. Clinvar id is 259344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75125255-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.6479A>T	p.Glu2160Val	missense_variant	40/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.6479A>T	p.Glu2160Val	missense_variant	40/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.2987A>T	p.Glu996Val	missense_variant	25/51	1
COL12A1	ENST00000483888.6	c.6479A>T	p.Glu2160Val	missense_variant	40/65	5		A1
COL12A1	ENST00000416123.6	c.6479A>T	p.Glu2160Val	missense_variant	39/63	5

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5235 AN: 152082 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0343 AC: 8376 AN: 243970 Hom.: 199 AF XY: 0.0348 AC XY: 4599 AN XY: 132278

Gnomad AFR exome AF: 0.00711

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.00691

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0511

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0446 AC: 64952 AN: 1455194 Hom.: 1729 Cov.: 31 AF XY: 0.0438 AC XY: 31702 AN XY: 723574

Gnomad4 AFR exome AF: 0.00704

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00701

Gnomad4 FIN exome AF: 0.0574

Gnomad4 NFE exome AF: 0.0513

Gnomad4 OTH exome AF: 0.0393

GnomAD4 genome AF: 0.0344 AC: 5233 AN: 152200 Hom.: 135 Cov.: 32 AF XY: 0.0337 AC XY: 2511 AN XY: 74424

Gnomad4 AFR AF: 0.00845

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0574

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0471 Hom.: 140

Bravo AF: 0.0312

TwinsUK AF: 0.0494 AC: 183

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.00924 AC: 35

ESP6500EA AF: 0.0474 AC: 390

ExAC AF: 0.0334 AC: 4037

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0503

EpiControl AF: 0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	0.33
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.080	T;T;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.54
MPC		1.5
ClinPred		0.0069	T
GERP RS		5.2
Varity_R		0.63
gMVP		0.70

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: rs35523808; hg19: chr6-75834971; COSMIC: COSV59396934;