rs240736

chr6-75138465-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004370.6(COL12A1):c.5213T>C(p.Ile1738Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,334 control chromosomes in the GnomAD database, including 64,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1738M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (6440 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57941 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.403

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029047132).
• BP6: Variant 6-75138465-A-G is Benign according to our data. Variant chr6-75138465-A-G is described in ClinVar as [Benign]. Clinvar id is 259336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75138465-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.5213T>C	p.Ile1738Thr	missense_variant	29/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.5213T>C	p.Ile1738Thr	missense_variant	29/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44099 AN: 151970 Hom.: 6440 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.264 AC: 65633 AN: 248634 Hom.: 9011 AF XY: 0.263 AC XY: 35417 AN XY: 134886

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.279 AC: 407739 AN: 1461246 Hom.: 57941 Cov.: 35 AF XY: 0.277 AC XY: 201551 AN XY: 726876

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.290 AC: 44110 AN: 152088 Hom.: 6440 Cov.: 32 AF XY: 0.286 AC XY: 21231 AN XY: 74346

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.288

Gnomad4 OTH AF: 0.294

Alfa AF: 0.284 Hom.: 15656

Bravo AF: 0.296

TwinsUK AF: 0.305 AC: 1132

ALSPAC AF: 0.267 AC: 1029

ESP6500AA AF: 0.308 AC: 1179

ESP6500EA AF: 0.285 AC: 2364

ExAC AF: 0.264 AC: 31933

Asia WGS AF: 0.197 AC: 690 AN: 3476

EpiCase AF: 0.287

EpiControl AF: 0.291

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Bethlem myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Ullrich congenital muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.91
Dann	Benign	0.54
DEOGEN2	Benign	0.0026	T;T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.83	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.015
MPC		0.15
ClinPred		0.0080	T
GERP RS		-12
Varity_R		0.028
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs240736; hg19: chr6-75848181; COSMIC: COSV59391375; COSMIC: COSV59391375;