NM_001846.4:c.551G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001846.4(COL4A2):​c.551G>T​(p.Gly184Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G184D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

COL4A2
NM_001846.4 missense, splice_region

Scores

12
5
2
Splicing: ADA: 0.005670
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12
Variant links:
Genes affected
COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A2NM_001846.4 linkc.551G>T p.Gly184Val missense_variant, splice_region_variant Exon 9 of 48 ENST00000360467.7 NP_001837.2 P08572A0A024RDW8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A2ENST00000360467.7 linkc.551G>T p.Gly184Val missense_variant, splice_region_variant Exon 9 of 48 5 NM_001846.4 ENSP00000353654.5 P08572
COL4A2ENST00000650540.1 linkc.551G>T p.Gly184Val missense_variant, splice_region_variant Exon 9 of 18 ENSP00000497878.1 A0A3B3ITQ8
COL4A2ENST00000462309.2 linkn.352G>T non_coding_transcript_exon_variant Exon 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jan 06, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.60
D;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.74
T;T
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.3
D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.0020
D;.
Polyphen
1.0
D;.
Vest4
0.94
MutPred
0.65
Loss of methylation at R183 (P = 0.0775);Loss of methylation at R183 (P = 0.0775);
MVP
0.98
MPC
1.2
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.63
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0057
dbscSNV1_RF
Benign
0.040
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-111082749; API