rs77094372

Variant names:

• chr6-75123971-C-T
• rs77094372
• NM_004370.6:c.6848G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.6848G>A​(p.Gly2283Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00211 in 1,613,300 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (26 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063426495).
• BP6: Variant 6-75123971-C-T is Benign according to our data. Variant chr6-75123971-C-T is described in ClinVar as [Benign]. Clinvar id is 475891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75123971-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1630/152250) while in subpopulation AFR AF= 0.0367 (1524/41542). AF 95% confidence interval is 0.0352. There are 25 homozygotes in gnomad4. There are 776 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.6848G>A	p.Gly2283Glu	missense_variant	Exon 42 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.6848G>A	p.Gly2283Glu	missense_variant	Exon 42 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.3356G>A	p.Gly1119Glu	missense_variant	Exon 27 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.6848G>A	p.Gly2283Glu	missense_variant	Exon 42 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.6848G>A	p.Gly2283Glu	missense_variant	Exon 41 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 152132 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00261 AC: 650 AN: 248698 Hom.: 11 AF XY: 0.00202 AC XY: 273 AN XY: 134914

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00121 AC: 1774 AN: 1461050 Hom.: 26 Cov.: 31 AF XY: 0.00109 AC XY: 793 AN XY: 726694

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00213

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: 0.000198

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152250 Hom.: 25 Cov.: 32 AF XY: 0.0104 AC XY: 776 AN XY: 74444

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00197 Hom.: 7

Bravo AF: 0.0116

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0344 AC: 128

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.00322 AC: 389

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.000491

EpiControl AF: 0.000712

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
MetaRNN	Benign	0.0063	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	.;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.041	.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.
Vest4		0.32
MVP		0.44
MPC		1.5
ClinPred		0.016	T
GERP RS		5.5
Varity_R		0.24
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77094372; hg19: chr6-75833687;