rs16886258

Positions:

• chr6-75188525-A-C

Variant summary

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

The ENST00000322507.13(COL12A1):​c.834T>G​(p.Ala278=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,612,462 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (49 hom.)
• Consequence: COL12A1 ENST00000322507.13 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.695

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=-0.53).
• BP6: Variant 6-75188525-A-C is Benign according to our data. Variant chr6-75188525-A-C is described in ClinVar as [Benign]. Clinvar id is 259352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75188525-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.695 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2028/152242) while in subpopulation AFR AF= 0.0465 (1934/41556). AF 95% confidence interval is 0.0448. There are 41 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.834T>G	p.Ala278=	synonymous_variant	8/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.834T>G	p.Ala278=	synonymous_variant	8/66	1	NM_004370.6	ENSP00000325146	P4
COL12A1	ENST00000345356.10	c.73+14195T>G		intron_variant		1		ENSP00000305147
COL12A1	ENST00000483888.6	c.834T>G	p.Ala278=	synonymous_variant	8/65	5		ENSP00000421216	A1
COL12A1	ENST00000416123.6	c.834T>G	p.Ala278=	synonymous_variant	7/63	5		ENSP00000412864

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2022 AN: 152124 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00355 AC: 879 AN: 247726 Hom.: 24 AF XY: 0.00271 AC XY: 364 AN XY: 134434

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00247

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00141 AC: 2055 AN: 1460220 Hom.: 49 Cov.: 31 AF XY: 0.00117 AC XY: 849 AN XY: 726430

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000936

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.0133 AC: 2028 AN: 152242 Hom.: 41 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74434

Gnomad4 AFR AF: 0.0465

Gnomad4 AMR AF: 0.00485

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00545 Hom.: 9

Bravo AF: 0.0156

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.79

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: rs16886258; hg19: chr6-75898241;