chr13-110430402-G-T

Variant names:

• chr13-110430402-G-T
• rs1555328401
• NM_001846.4:c.551G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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: Splicing: ADA: 0.005670
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

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]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
COL4A2	NM_001846.4	c.551G>T	p.Gly184Val	missense_variant, splice_region_variant	Exon 9 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.551G>T	p.Gly184Val	missense_variant, splice_region_variant	Exon 9 of 48	5	NM_001846.4	ENSP00000353654.5

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

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;.
PhyloP100		6.1
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
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1555328401; hg19: chr13-111082749;