rs186035636

Positions:

• chr6-75132003-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004370.6(COL12A1):​c.5874A>G​(p.Pro1958=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,614,174 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.99

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-75132003-T-C is Benign according to our data. Variant chr6-75132003-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75132003-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0027 (411/152334) while in subpopulation NFE AF= 0.00323 (220/68034). AF 95% confidence interval is 0.00288. There are 1 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.5874A>G	p.Pro1958=	synonymous_variant	35/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.5874A>G	p.Pro1958=	synonymous_variant	35/66	1	NM_004370.6	ENSP00000325146	P4
COL12A1	ENST00000345356.10	c.2382A>G	p.Pro794=	synonymous_variant	20/51	1		ENSP00000305147
COL12A1	ENST00000483888.6	c.5874A>G	p.Pro1958=	synonymous_variant	35/65	5		ENSP00000421216	A1
COL12A1	ENST00000416123.6	c.5874A>G	p.Pro1958=	synonymous_variant	34/63	5		ENSP00000412864

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00257 AC: 642 AN: 249338 Hom.: 2 AF XY: 0.00242 AC XY: 327 AN XY: 135260

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00213 AC: 3121 AN: 1461840 Hom.: 4 Cov.: 29 AF XY: 0.00215 AC XY: 1560 AN XY: 727224

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74480

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.00323

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL12A1: BP4, BP7 -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.025
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs186035636; hg19: chr6-75841719;