chr6-75113256-A-G

Variant names:

• chr6-75113256-A-G
• rs200408101
• NM_004370.6:c.7898T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001424113.1(COL12A1):​c.7898T>C​(p.Val2633Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,565,532 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: COL12A1 NM_001424113.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.85
• 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: 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009590089).
• BP6: Variant 6-75113256-A-G is Benign according to our data. Variant chr6-75113256-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259348.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00107 (162/151886) while in subpopulation AFR AF = 0.00303 (126/41536). AF 95% confidence interval is 0.0026. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.7898T>C	p.Val2633Ala	missense	Exon 51 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.7898T>C	p.Val2633Ala	missense	Exon 51 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.7877T>C	p.Val2626Ala	missense	Exon 50 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.7898T>C	p.Val2633Ala	missense	Exon 51 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.4406T>C	p.Val1469Ala	missense	Exon 36 of 51	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.7898T>C	p.Val2633Ala	missense	Exon 51 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 151768 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000347 AC: 76 AN: 218968 AF XY: 0.000317

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000863

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000975

GnomAD4 exome AF: 0.000247 AC: 349 AN: 1413646 Hom.: 3 Cov.: 29 AF XY: 0.000235 AC XY: 165 AN XY: 702086

African (AFR) AF: 0.00526 AC: 163 AN: 30972

American (AMR) AF: 0.000440 AC: 17 AN: 38624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.000434 AC: 16 AN: 36904

South Asian (SAS) AF: 0.000208 AC: 16 AN: 77012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50632

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5634

European-Non Finnish (NFE) AF: 0.0000688 AC: 75 AN: 1090748

Other (OTH) AF: 0.000931 AC: 54 AN: 58008

GnomAD4 genome AF: 0.00107 AC: 162 AN: 151886 Hom.: 0 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74250

African (AFR) AF: 0.00303 AC: 126 AN: 41536

American (AMR) AF: 0.000788 AC: 12 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67746

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000494 Hom.: 1

Bravo AF: 0.00108

ESP6500AA AF: 0.00193 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000439 AC: 53

Asia WGS AF: 0.00380 AC: 13 AN: 3440

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.9
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.046
Sift	Benign	0.14	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.33
MPC		0.62
ClinPred		0.015	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.50
Mutation Taster		=83/17	polymorphism

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: rs200408101; hg19: chr6-75822972;