rs181511246

chr6-75138914-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_004370.6(COL12A1):c.5005G>C(p.Glu1669Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,614,100 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.24

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0123901665).
• BP6: Variant 6-75138914-C-G is Benign according to our data. Variant chr6-75138914-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 475871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75138914-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (220/152316) while in subpopulation NFE AF= 0.0025 (170/68026). AF 95% confidence interval is 0.00219. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5005G>C	p.Glu1669Gln	missense_variant	28/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5005G>C	p.Glu1669Gln	missense_variant	28/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00108 AC: 269 AN: 248878 Hom.: 1 AF XY: 0.00100 AC XY: 135 AN XY: 135030

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.00242 AC: 3534 AN: 1461784 Hom.: 8 Cov.: 31 AF XY: 0.00227 AC XY: 1649 AN XY: 727188

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00300

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74486

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00225 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00220 AC: 18

ExAC AF: 0.000836 AC: 101

EpiCase AF: 0.00169

EpiControl AF: 0.00172

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	COL12A1: BP4, BS2 -

COL12A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Benign	0.86
DEOGEN2	Benign	0.020	T;T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
Sift4G	Uncertain	0.0070	D;T;D;T;T
Polyphen		0.25, 0.21	.;B;B;.;.
Vest4		0.060
MVP		0.32
MPC		0.12
ClinPred		0.0051	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs181511246; hg19: chr6-75848630;