rs34369939

Positions:

• chr6-75105234-A-G
• chr6-75105234-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.8237T>C​(p.Val2746Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,766 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V2746I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (110 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.67

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=0.008241266).
• BP6: Variant 6-75105234-A-G is Benign according to our data. Variant chr6-75105234-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75105234-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00911 (1387/152262) while in subpopulation NFE AF= 0.01 (682/68024). AF 95% confidence interval is 0.0094. There are 12 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.8237T>C	p.Val2746Ala	missense_variant	54/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.8237T>C	p.Val2746Ala	missense_variant	54/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1388 AN: 152144 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00961 AC: 2395 AN: 249184 Hom.: 22 AF XY: 0.00956 AC XY: 1293 AN XY: 135184

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0285

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00778

GnomAD4 exome AF: 0.0111 AC: 16155 AN: 1461504 Hom.: 110 Cov.: 30 AF XY: 0.0108 AC XY: 7850 AN XY: 727044

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152262 Hom.: 12 Cov.: 32 AF XY: 0.00970 AC XY: 722 AN XY: 74456

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0347

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0102 Hom.: 18

Bravo AF: 0.00681

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00214 AC: 8

ESP6500EA AF: 0.0126 AC: 104

ExAC AF: 0.00924 AC: 1116

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COL12A1: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.052
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
MetaRNN	Benign	0.0082	T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	0.59	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.14	N;.;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.82	T;.;T;T;T;T
Sift4G	Benign	0.95	T;T;T;T;T;T
Polyphen		0.87, 0.71	.;.;P;P;.;.
Vest4		0.37, 0.49, 0.41, 0.47, 0.37
MVP		0.80
MPC		0.85
ClinPred		0.034	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34369939; hg19: chr6-75814950; COSMIC: COSV59409649; COSMIC: COSV59409649;