rs75535959

chr6-75189584-T-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.626A>C(p.Lys209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,054 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (127 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.630

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=0.0027424395).
• BP6: Variant 6-75189584-T-G is Benign according to our data. Variant chr6-75189584-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 475885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75189584-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.626A>C	p.Lys209Thr	missense_variant	6/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.626A>C	p.Lys209Thr	missense_variant	6/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.73+13136A>C		intron_variant		1
COL12A1	ENST00000483888.6	c.626A>C	p.Lys209Thr	missense_variant	6/65	5		A1
COL12A1	ENST00000416123.6	c.626A>C	p.Lys209Thr	missense_variant	5/63	5

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3414 AN: 152078 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00879

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00565 AC: 1395 AN: 246950 Hom.: 40 AF XY: 0.00449 AC XY: 602 AN XY: 134190

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00230 AC: 3361 AN: 1460858 Hom.: 127 Cov.: 32 AF XY: 0.00198 AC XY: 1439 AN XY: 726696

Gnomad4 AFR exome AF: 0.0817

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.0225 AC: 3421 AN: 152196 Hom.: 112 Cov.: 32 AF XY: 0.0212 AC XY: 1580 AN XY: 74428

Gnomad4 AFR AF: 0.0780

Gnomad4 AMR AF: 0.00878

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00416 Hom.: 28

Bravo AF: 0.0259

ESP6500AA AF: 0.0767 AC: 278

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00680 AC: 821

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	11
Dann	Benign	0.97
DEOGEN2	Benign	0.097	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.17	N;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.010	B;.;.
Vest4		0.30
MVP		0.42
MPC		0.17
ClinPred		0.0031	T
GERP RS		0.43
Varity_R		0.048
gMVP		0.71

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: rs75535959; hg19: chr6-75899300;