3-130563203-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A6NM_001102608.3 linkc.200C>T p.Ala67Val missense_variant Exon 3 of 37 ENST00000358511.11 NP_001096078.1 A6NMZ7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A6ENST00000358511.11 linkc.200C>T p.Ala67Val missense_variant Exon 3 of 37 5 NM_001102608.3 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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 23, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.200C>T (p.A67V) alteration is located in exon 2 (coding exon 2) of the COL6A6 gene. This alteration results from a C to T substitution at nucleotide position 200, causing the alanine (A) at amino acid position 67 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2062934727; hg19: chr3-130282047; API