rs191233787

Variant names:

• chr6-75132038-G-A
• rs191233787
• NM_004370.6:c.5839C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-75132038-G-A
• chr6-75132038-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004370.6(COL12A1):​c.5839C>T​(p.Pro1947Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1947L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.62
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17275718).
• BP6: Variant 6-75132038-G-A is Benign according to our data. Variant chr6-75132038-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 940839.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5839C>T	p.Pro1947Ser	missense_variant	Exon 35 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5839C>T	p.Pro1947Ser	missense_variant	Exon 35 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.2347C>T	p.Pro783Ser	missense_variant	Exon 20 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.5839C>T	p.Pro1947Ser	missense_variant	Exon 35 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.5839C>T	p.Pro1947Ser	missense_variant	Exon 34 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249256 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000331 AC: 4

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

Oct 30, 2024

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	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T;T;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;.;L;.
PhyloP100		2.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	.;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.56	.;T;T;T;T
Sift4G	Uncertain	0.055	T;D;T;D;D
Polyphen		0.70, 0.65	.;P;P;.;.
Vest4		0.40
MutPred		0.34		.;Gain of MoRF binding (P = 0.0587);.;Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);
MVP		0.40
MPC		0.43
ClinPred		0.26	T
GERP RS		6.2
Varity_R		0.088
gMVP		0.48
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs191233787; hg19: chr6-75841754; COSMIC: COSV107376894; COSMIC: COSV107376894;