rs200201449

chr6-75138457-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BP6 BS1

The NM_004370.6(COL12A1):c.5221G>A(p.Glu1741Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,613,348 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.68

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-75138457-C-T is Benign according to our data. Variant chr6-75138457-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000453 (69/152288) while in subpopulation SAS AF= 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5221G>A	p.Glu1741Lys	missense_variant	29/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5221G>A	p.Glu1741Lys	missense_variant	29/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000842 AC: 209 AN: 248142 Hom.: 1 AF XY: 0.000877 AC XY: 118 AN XY: 134586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00630

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000710

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000483 AC: 705 AN: 1461060 Hom.: 2 Cov.: 31 AF XY: 0.000527 AC XY: 383 AN XY: 726764

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.00529

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000904 Hom.: 0

Bravo AF: 0.000514

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000843 AC: 7

ExAC AF: 0.000803 AC: 97

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		0.81, 0.88	.;P;P;.;.
Vest4		0.71
MVP		0.96
MPC		0.60
ClinPred		0.068	T
GERP RS		5.8
Varity_R		0.24
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200201449; hg19: chr6-75848173; COSMIC: COSV99072102; COSMIC: COSV99072102;