rs191233787

chr6-75132038-G-Achr6-75132038-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 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. 14/21 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. P1947T) 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

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL12A1
• 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 id is 940839.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5839C>T	p.Pro1947Ser	missense_variant	35/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5839C>T	p.Pro1947Ser	missense_variant	35/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.2347C>T	p.Pro783Ser	missense_variant	20/51	1
COL12A1	ENST00000483888.6	c.5839C>T	p.Pro1947Ser	missense_variant	35/65	5		A1
COL12A1	ENST00000416123.6	c.5839C>T	p.Pro1947Ser	missense_variant	34/63	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249256 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135210

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2023

- -

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
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.53	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

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

Publications

LitVar

Other links and lift over

dbSNP: rs191233787; hg19: chr6-75841754;