rs1555328401

chr13-110430402-G-Achr13-110430402-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001846.4(COL4A2):c.551G>A(p.Gly184Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 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. G184V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL4A2 NM_001846.4 missense, splice_region
• Scores: Splicing: ADA: 0.4932
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

ACMG classification

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, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.551G>A	p.Gly184Asp	missense_variant, splice_region_variant	9/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.551G>A	p.Gly184Asp	missense_variant, splice_region_variant	9/48	5	NM_001846.4	P1
COL4A2	ENST00000650540.1	c.551G>A	p.Gly184Asp	missense_variant, splice_region_variant	9/18
COL4A2	ENST00000462309.2	n.352G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461444 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joint hypermobility Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.65		Loss of methylation at R183 (P = 0.0497);Loss of methylation at R183 (P = 0.0497);
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.33
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

Other links and lift over

dbSNP: rs1555328401; hg19: chr13-111082749;