rs391859

Positions:

• chr13-110507957-G-A

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.4617G>A​(p.Ala1539Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,613,750 control chromosomes in the GnomAD database, including 7,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (795 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6523 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.66

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-110507957-G-A is Benign according to our data. Variant chr13-110507957-G-A is described in ClinVar as [Benign]. Clinvar id is 311183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110507957-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.4617G>A	p.Ala1539Ala	synonymous_variant	47/48	ENST00000360467.7	NP_001837.2
COL4A2-AS1	NR_046583.1	n.81+142C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.4617G>A	p.Ala1539Ala	synonymous_variant	47/48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14296 AN: 152048 Hom.: 791 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0871

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.106 AC: 26210 AN: 248338 Hom.: 1795 AF XY: 0.101 AC XY: 13681 AN XY: 134822

Gnomad AFR exome AF: 0.0797

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.0652

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0872

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0876 AC: 128031 AN: 1461584 Hom.: 6523 Cov.: 31 AF XY: 0.0873 AC XY: 63503 AN XY: 727056

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.0691

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0810

Gnomad4 OTH exome AF: 0.0972

GnomAD4 genome AF: 0.0941 AC: 14319 AN: 152166 Hom.: 795 Cov.: 32 AF XY: 0.0930 AC XY: 6922 AN XY: 74422

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.0462

Gnomad4 NFE AF: 0.0871

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0974 Hom.: 1127

Bravo AF: 0.106

Asia WGS AF: 0.103 AC: 358 AN: 3478

EpiCase AF: 0.0959

EpiControl AF: 0.0968

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Porencephaly 2 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.24
DANN	Benign	0.88

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

Other links and lift over

dbSNP: rs391859; hg19: chr13-111160304; COSMIC: COSV64627362;