rs4238272

Positions:

• chr13-110424850-G-A
• chr13-110424850-G-C

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.297G>A​(p.Thr99Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,614,068 control chromosomes in the GnomAD database, including 745,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67054 hom., cov: 31)
  • Exomes 𝑓: 0.96 (678191 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.795

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=-0.84).
• BP6: Variant 13-110424850-G-A is Benign according to our data. Variant chr13-110424850-G-A is described in ClinVar as [Benign]. Clinvar id is 311096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110424850-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.795 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.297G>A	p.Thr99Thr	synonymous_variant	5/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.297G>A	p.Thr99Thr	synonymous_variant	5/48	5	NM_001846.4	ENSP00000353654.5
COL4A2	ENST00000650540.1	c.297G>A	p.Thr99Thr	synonymous_variant	5/18			ENSP00000497878.1
COL4A2	ENST00000400163.7	c.297G>A	p.Thr99Thr	synonymous_variant	5/5	5		ENSP00000383027.4
COL4A2	ENST00000619688.2	c.48G>A	p.Thr16Thr	synonymous_variant	1/3	6		ENSP00000496868.2

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142587 AN: 152124 Hom.: 67015 Cov.: 31

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.985

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.987

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.961

Gnomad OTH AF: 0.950

GnomAD3 exomes AF: 0.964 AC: 240599 AN: 249490 Hom.: 116123 AF XY: 0.965 AC XY: 130685 AN XY: 135362

Gnomad AFR exome AF: 0.854

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.971

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.961

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.963 AC: 1407681 AN: 1461826 Hom.: 678191 Cov.: 50 AF XY: 0.963 AC XY: 700486 AN XY: 727218

Gnomad4 AFR exome AF: 0.851

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.981

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.971

Gnomad4 FIN exome AF: 0.984

Gnomad4 NFE exome AF: 0.962

Gnomad4 OTH exome AF: 0.959

GnomAD4 genome AF: 0.937 AC: 142684 AN: 152242 Hom.: 67054 Cov.: 31 AF XY: 0.938 AC XY: 69838 AN XY: 74430

Gnomad4 AFR AF: 0.859

Gnomad4 AMR AF: 0.964

Gnomad4 ASJ AF: 0.979

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.973

Gnomad4 FIN AF: 0.987

Gnomad4 NFE AF: 0.961

Gnomad4 OTH AF: 0.950

Alfa AF: 0.949 Hom.: 43808

Bravo AF: 0.934

Asia WGS AF: 0.977 AC: 3397 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	Mar 03, 2015	- -
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: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	-0.84
CADD	Benign	0.090
DANN	Benign	0.66

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: rs4238272; hg19: chr13-111077197;