chr6-75124067-C-T

Variant names:

• chr6-75124067-C-T
• rs151324784
• NM_004370.6:c.6752G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):​c.6752G>A​(p.Arg2251His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R2251C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.81
• Publications: 7 publications found

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]

COL12A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
• Ullrich congenital muscular dystrophy 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019210845).
• BP6: Variant 6-75124067-C-T is Benign according to our data. Variant chr6-75124067-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542522.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000374 (57/152268) while in subpopulation NFE AF = 0.00047 (32/68018). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.6752G>A	p.Arg2251His	missense	Exon 42 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.6752G>A	p.Arg2251His	missense	Exon 42 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.6731G>A	p.Arg2244His	missense	Exon 41 of 65	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.6752G>A	p.Arg2251His	missense	Exon 42 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.3260G>A	p.Arg1087His	missense	Exon 27 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.6752G>A	p.Arg2251His	missense	Exon 42 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000409 AC: 102 AN: 249116 AF XY: 0.000400

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000487

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000317 AC: 464 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.000345 AC XY: 251 AN XY: 726968

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000157 AC: 7 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 78 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86226

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000288 AC: 320 AN: 1111686

Other (OTH) AF: 0.000331 AC: 20 AN: 60382

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74438

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.000372 AC: 45

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Aug 12, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL12A1: BS1

Oct 31, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Feb 05, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL12A1 c.6752G>A (p.Arg2251His) results in a non-conservative amino acid change located in the Fibronectin type 3 domain (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 0.00041 in 249116 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL12A1 causing Ullrich congenital muscular dystrophy 2 (0.00041 vs 0.0035), allowing no conclusion about variant significance. c.6752G>A has been reported in the literature in at least one individual affected with skeletal muscle weakness without evidence of causality (e.g. Jarmula_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Ullrich congenital muscular dystrophy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31395899). ClinVar contains an entry for this variant (Variation ID: 542522). Based on the evidence outlined above, the variant was classified as uncertain significance.

COL12A1-related disorder Benign:1

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.12
Sift	Benign	0.067	T
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.35
MPC		1.0
ClinPred		0.076	T
GERP RS		5.3
Varity_R		0.089
gMVP		0.37
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs151324784; hg19: chr6-75833783; COSMIC: COSV59395949; COSMIC: COSV59395949;