rs200450866

Variant names:

• chr6-75126363-A-G
• rs200450866
• NM_004370.6:c.6448T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_004370.6(COL12A1):​c.6448T>C​(p.Tyr2150His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2150C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 8.95

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 -5 ACMG points.

• BP6: Variant 6-75126363-A-G is Benign according to our data. Variant chr6-75126363-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475888.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152154) while in subpopulation AMR AF= 0.00118 (18/15254). AF 95% confidence interval is 0.000762. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.6448T>C	p.Tyr2150His	missense_variant	Exon 39 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.6448T>C	p.Tyr2150His	missense_variant	Exon 39 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.2956T>C	p.Tyr986His	missense_variant	Exon 24 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.6448T>C	p.Tyr2150His	missense_variant	Exon 39 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.6448T>C	p.Tyr2150His	missense_variant	Exon 38 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000313 AC: 78 AN: 248840 Hom.: 0 AF XY: 0.000274 AC XY: 37 AN XY: 134992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000299 AC: 436 AN: 1457830 Hom.: 0 Cov.: 30 AF XY: 0.000309 AC XY: 224 AN XY: 725236

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.000616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74336

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000331 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with limb-girdle muscular dystrophy (LGMD) who also harbored a pathogenic variant in the CAPN3 gene (PMID: 29970176); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970176) -

Oct 26, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL12A1 c.6448T>C (p.Tyr2150His) results in a conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 248840 control chromosomes. The observed variant frequency is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL12A1 causing Bethlem myopathy 2 phenotype (1e-06). To our knowledge, no occurrence of c.6448T>C in individuals affected with Bethlem myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 475888). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.0014	D
MutationAssessor	Uncertain	2.9	.;M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	.;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.90
MVP		0.81
MPC		1.6
ClinPred		0.21	T
GERP RS		5.7
Varity_R		0.87
gMVP		0.84

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: rs200450866; hg19: chr6-75836079; COSMIC: COSV59388646;