chr13-110449695-G-A

Position:

• chr13-110449695-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.1095G>A​(p.Pro365Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,547,466 control chromosomes in the GnomAD database, including 100,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7158 hom., cov: 32)
  • Exomes 𝑓: 0.36 (93534 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.375

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-110449695-G-A is Benign according to our data. Variant chr13-110449695-G-A is described in ClinVar as [Benign]. Clinvar id is 311119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110449695-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.375 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1095G>A	p.Pro365Pro	synonymous_variant	19/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1095G>A	p.Pro365Pro	synonymous_variant	19/48	5	NM_001846.4	ENSP00000353654.5
COL4A2	ENST00000617564.2	c.351G>A	p.Pro117Pro	synonymous_variant	7/10	6		ENSP00000481492.3

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43333 AN: 151838 Hom.: 7153 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.309 AC: 47279 AN: 152798 Hom.: 7986 AF XY: 0.317 AC XY: 25661 AN XY: 81018

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.326

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.361 AC: 503171 AN: 1395510 Hom.: 93534 Cov.: 35 AF XY: 0.361 AC XY: 248155 AN XY: 687962

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.407

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.327

GnomAD4 genome AF: 0.285 AC: 43341 AN: 151956 Hom.: 7158 Cov.: 32 AF XY: 0.286 AC XY: 21206 AN XY: 74264

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.260

Alfa AF: 0.335 Hom.: 4650

Bravo AF: 0.260

Asia WGS AF: 0.278 AC: 970 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 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	Jan 31, 2024	- -

Porencephaly 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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	-0.62
CADD	Benign	3.6
DANN	Benign	0.79

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: rs76425569; hg19: chr13-111102042; COSMIC: COSV64626275;