rs34846477

Positions:

• chr6-75089136-A-G

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.8980T>C​(p.Ser2994Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,611,696 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66

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=0.004817128).
• BP6: Variant 6-75089136-A-G is Benign according to our data. Variant chr6-75089136-A-G is described in ClinVar as [Benign]. Clinvar id is 259355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75089136-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.8980T>C	p.Ser2994Pro	missense_variant	64/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.8980T>C	p.Ser2994Pro	missense_variant	64/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2250 AN: 152134 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00373 AC: 917 AN: 246116 Hom.: 14 AF XY: 0.00285 AC XY: 381 AN XY: 133736

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00166 AC: 2420 AN: 1459444 Hom.: 51 Cov.: 30 AF XY: 0.00152 AC XY: 1101 AN XY: 726138

Gnomad4 AFR exome AF: 0.0530

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.0150 AC: 2278 AN: 152252 Hom.: 51 Cov.: 32 AF XY: 0.0148 AC XY: 1105 AN XY: 74452

Gnomad4 AFR AF: 0.0513

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00160 Hom.: 8

Bravo AF: 0.0172

ESP6500AA AF: 0.0523 AC: 190

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00469 AC: 566

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000357

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.12	T;T;T;T;T;T
MetaRNN	Benign	0.0048	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.12	N;.;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.50	T;.;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;.;.
Vest4		0.14, 0.23, 0.14, 0.17, 0.20
MVP		0.39
MPC		0.60
ClinPred		0.0056	T
GERP RS		5.0
Varity_R		0.077
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34846477; hg19: chr6-75798852;