6-75133320-C-T

Variant names:

• chr6-75133320-C-T
• rs764600940
• NM_004370.6:c.5767G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_004370.6(COL12A1):​c.5767G>A​(p.Gly1923Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,448,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. G1923A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.51
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34569594).
• BP6: Variant 6-75133320-C-T is Benign according to our data. Variant chr6-75133320-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 579860.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5767G>A	p.Gly1923Arg	missense_variant	Exon 34 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5767G>A	p.Gly1923Arg	missense_variant	Exon 34 of 66	1	NM_004370.6	ENSP00000325146.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 242888 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000828 AC: 12 AN: 1448884 Hom.: 0 Cov.: 31 AF XY: 0.00000833 AC XY: 6 AN XY: 719970

African (AFR) AF: 0.00 AC: 0 AN: 33018

American (AMR) AF: 0.00 AC: 0 AN: 43314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39280

South Asian (SAS) AF: 0.00 AC: 0 AN: 82390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106314

Other (OTH) AF: 0.0000835 AC: 5 AN: 59886

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 19, 2023

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	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	.;M;.;M;.
PhyloP100		3.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.78	.;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.28	.;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.98, 0.93	.;D;P;.;.
Vest4		0.46
MutPred		0.68		.;Gain of MoRF binding (P = 0.0226);.;Gain of MoRF binding (P = 0.0226);Gain of MoRF binding (P = 0.0226);
MVP		0.51
MPC		0.59
ClinPred		0.26	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.46
Mutation Taster		=88/12	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: rs764600940; hg19: chr6-75843036;