chr6-75165718-A-G

Variant names:

• chr6-75165718-A-G
• rs35429515
• NM_004370.6:c.2772T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004370.6(COL12A1):​c.2772T>C​(p.Tyr924Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,006 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (106 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.162
• Publications: 1 publications found

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]

COL12A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Illumina, Ambry Genetics, Genomics England PanelApp
• Ullrich congenital muscular dystrophy 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 6-75165718-A-G is Benign according to our data. Variant chr6-75165718-A-G is described in ClinVar as Benign. ClinVar VariationId is 259327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.2772T>C	p.Tyr924Tyr	synonymous	Exon 14 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.2772T>C	p.Tyr924Tyr	synonymous	Exon 14 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.2772T>C	p.Tyr924Tyr	synonymous	Exon 14 of 65	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.2772T>C	p.Tyr924Tyr	synonymous	Exon 14 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.74-13236T>C		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.2772T>C	p.Tyr924Tyr	synonymous	Exon 14 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3490 AN: 152168 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00615 AC: 1533 AN: 249310 AF XY: 0.00461

Gnomad AFR exome AF: 0.0827

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00246 AC: 3591 AN: 1461720 Hom.: 106 Cov.: 31 AF XY: 0.00215 AC XY: 1561 AN XY: 727158

African (AFR) AF: 0.0822 AC: 2751 AN: 33474

American (AMR) AF: 0.00615 AC: 275 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.000176 AC: 196 AN: 1111898

Other (OTH) AF: 0.00488 AC: 295 AN: 60392

GnomAD4 genome AF: 0.0230 AC: 3496 AN: 152286 Hom.: 123 Cov.: 32 AF XY: 0.0221 AC XY: 1648 AN XY: 74462

African (AFR) AF: 0.0786 AC: 3268 AN: 41556

American (AMR) AF: 0.0109 AC: 166 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.00977 Hom.: 39

Bravo AF: 0.0268

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.33
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35429515; hg19: chr6-75875434;