rs4773199

Positions:

• chr13-110503432-G-A
• chr13-110503432-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.4089G>A​(p.Ala1363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,587,136 control chromosomes in the GnomAD database, including 39,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4258 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34755 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.423

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-AS1 (HGNC:40156): (COL4A2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 13-110503432-G-A is Benign according to our data. Variant chr13-110503432-G-A is described in ClinVar as [Benign]. Clinvar id is 311171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110503432-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.423 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.4089G>A	p.Ala1363=	synonymous_variant	43/48	ENST00000360467.7
COL4A2-AS1	NR_046583.1	n.187-504C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.4089G>A	p.Ala1363=	synonymous_variant	43/48	5	NM_001846.4	P1
COL4A2-AS1	ENST00000417970.2	n.187-504C>T		intron_variant, non_coding_transcript_variant		3
COL4A2	ENST00000650225.1	n.1744G>A		non_coding_transcript_exon_variant	14/19

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34564 AN: 152024 Hom.: 4257 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0442

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.196 AC: 40201 AN: 204648 Hom.: 4395 AF XY: 0.200 AC XY: 22191 AN XY: 110758

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.0538

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.215 AC: 307913 AN: 1434994 Hom.: 34755 Cov.: 34 AF XY: 0.215 AC XY: 152911 AN XY: 711708

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.227 AC: 34572 AN: 152142 Hom.: 4258 Cov.: 33 AF XY: 0.220 AC XY: 16350 AN XY: 74390

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0439

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.214

Alfa AF: 0.230 Hom.: 2146

Bravo AF: 0.233

Asia WGS AF: 0.158 AC: 550 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porencephaly 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.55
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4773199; hg19: chr13-111155779; COSMIC: COSV64626170; COSMIC: COSV64626170;