3-130563203-C-T

Variant names:

• chr3-130563203-C-T
• rs2062934727
• NM_001102608.3:c.200C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001102608.3(COL6A6):​c.200C>T​(p.Ala67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A6 NM_001102608.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• Publications: 0 publications found

Genes affected

COL6A6 (HGNC:27023): (collagen type VI alpha 6 chain) This gene encodes a large protein that contains multiple von Willebrand factor domains and forms a component of the basal lamina of epithelial cells. This protein may regulate epithelial cell-fibronectin interactions. Variation in this gene may be implicated in skin diseases. [provided by RefSeq, May 2017]

COL6A6 Gene-Disease associations (from GenCC):

• congenital myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics
• myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102608.3. 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
	COL6A6	NM_001102608.3	MANE Select	c.200C>T	p.Ala67Val	missense	Exon 3 of 37	NP_001096078.1	A6NMZ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A6	ENST00000358511.11	TSL:5 MANE Select	c.200C>T	p.Ala67Val	missense	Exon 3 of 37	ENSP00000351310.6	A6NMZ7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.65
MutPred		0.82		Loss of ubiquitination at K63 (P = 0.0992)
MVP		0.67
MPC		0.35
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.23
gMVP		0.77
Mutation Taster		=89/11	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: rs2062934727; hg19: chr3-130282047;