6-75125144-G-A

Variant names:

• chr6-75125144-G-A
• rs117038107
• NM_004370.6:c.6590C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.6590C>T​(p.Thr2197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,610,238 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (101 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.731
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041609406).
• BP6: Variant 6-75125144-G-A is Benign according to our data. Variant chr6-75125144-G-A is described in ClinVar as Benign. ClinVar VariationId is 475889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1175/152224) while in subpopulation NFE AF = 0.0102 (693/67992). AF 95% confidence interval is 0.00956. There are 5 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.6590C>T	p.Thr2197Ile	missense	Exon 40 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.6590C>T	p.Thr2197Ile	missense	Exon 40 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.6569C>T	p.Thr2190Ile	missense	Exon 39 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.6590C>T	p.Thr2197Ile	missense	Exon 40 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.3098C>T	p.Thr1033Ile	missense	Exon 25 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.6590C>T	p.Thr2197Ile	missense	Exon 40 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152106 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00868 AC: 2138 AN: 246304 AF XY: 0.00916

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00291

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.0108 AC: 15689 AN: 1458014 Hom.: 101 Cov.: 30 AF XY: 0.0108 AC XY: 7813 AN XY: 725210

African (AFR) AF: 0.00123 AC: 41 AN: 33330

American (AMR) AF: 0.00352 AC: 156 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 90 AN: 26026

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39534

South Asian (SAS) AF: 0.0101 AC: 863 AN: 85450

European-Finnish (FIN) AF: 0.0197 AC: 1051 AN: 53324

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5760

European-Non Finnish (NFE) AF: 0.0116 AC: 12821 AN: 1110032

Other (OTH) AF: 0.0106 AC: 640 AN: 60232

GnomAD4 genome AF: 0.00772 AC: 1175 AN: 152224 Hom.: 5 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74428

African (AFR) AF: 0.00202 AC: 84 AN: 41540

American (AMR) AF: 0.00608 AC: 93 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

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

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4826

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 67992

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00844 Hom.: 16

Bravo AF: 0.00637

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00263 AC: 10

ESP6500EA AF: 0.0119 AC: 98

ExAC AF: 0.00904 AC: 1093

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.0102

EpiControl AF: 0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL12A1: BP4, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.73
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.012
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.0070	B
Vest4		0.13
MVP		0.21
MPC		0.51
ClinPred		0.0035	T
GERP RS		3.4
Varity_R		0.082
gMVP		0.38
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs117038107; hg19: chr6-75834860;