rs75535959

Positions:

• 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 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=0.0027424395).
• 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	Protein	UniProt
COL12A1	NM_004370.6	c.626A>C	p.Lys209Thr	missense_variant	6/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.626A>C	p.Lys209Thr	missense_variant	6/66	1	NM_004370.6	ENSP00000325146	P4
COL12A1	ENST00000345356.10	c.73+13136A>C		intron_variant		1		ENSP00000305147
COL12A1	ENST00000483888.6	c.626A>C	p.Lys209Thr	missense_variant	6/65	5		ENSP00000421216	A1
COL12A1	ENST00000416123.6	c.626A>C	p.Lys209Thr	missense_variant	5/63	5		ENSP00000412864

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	Labcorp Genetics (formerly Invitae), Labcorp	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;