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 ENST00000322507.13(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 ENST00000322507.13 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 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=0.004817128).
• 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	Protein	UniProt
COL12A1	NM_004370.6	c.8980T>C	p.Ser2994Pro	missense_variant	64/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.8980T>C	p.Ser2994Pro	missense_variant	64/66	1	NM_004370.6	ENSP00000325146	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

Labcorp Genetics (formerly Invitae), Labcorp

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
DEOGEN2	Benign	0.0019	.;T;T;.;.;.
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
MutationAssessor	Benign	1.7	.;.;L;.;.;.
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;