chr13-110449779-C-T

Position:

• chr13-110449779-C-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.1179C>T​(p.Ile393Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,547,352 control chromosomes in the GnomAD database, including 116,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8265 hom., cov: 31)
  • Exomes 𝑓: 0.39 (107910 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.96

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=-0.7).
• BP6: Variant 13-110449779-C-T is Benign according to our data. Variant chr13-110449779-C-T is described in ClinVar as [Benign]. Clinvar id is 311120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110449779-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1179C>T	p.Ile393Ile	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.1179C>T	p.Ile393Ile	synonymous_variant	19/48	5	NM_001846.4	ENSP00000353654.5
COL4A2	ENST00000617564.2	c.435C>T	p.Ile145Ile	synonymous_variant	7/10	6		ENSP00000481492.3

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46296 AN: 151770 Hom.: 8261 Cov.: 31

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.331 AC: 50178 AN: 151472 Hom.: 9097 AF XY: 0.338 AC XY: 27190 AN XY: 80484

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.387 AC: 540031 AN: 1395464 Hom.: 107910 Cov.: 35 AF XY: 0.386 AC XY: 266009 AN XY: 688346

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.305 AC: 46296 AN: 151888 Hom.: 8265 Cov.: 31 AF XY: 0.306 AC XY: 22702 AN XY: 74252

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.280

Alfa AF: 0.343 Hom.: 3650

Bravo AF: 0.278

Asia WGS AF: 0.274 AC: 955 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.7
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74941798; hg19: chr13-111102126;