chr6-75154447-G-T

Variant names:

• chr6-75154447-G-T
• rs747982811
• NM_004370.6:c.3534C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001424113.1(COL12A1):​c.3534C>A​(p.Ser1178Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S1178S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_001424113.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet
• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 6-75154447-G-T is Benign according to our data. Variant chr6-75154447-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1986738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.084 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424113.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.3534C>A	p.Ser1178Ser	synonymous	Exon 17 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.3534C>A	p.Ser1178Ser	synonymous	Exon 17 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.3534C>A	p.Ser1178Ser	synonymous	Exon 17 of 65	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.3534C>A	p.Ser1178Ser	synonymous	Exon 17 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.74-1965C>A		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.3534C>A	p.Ser1178Ser	synonymous	Exon 17 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.52
PhyloP100		0.084

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: rs747982811; hg19: chr6-75864163; COSMIC: COSV59414573; COSMIC: COSV59414573;