rs7989823

chr13-110307296-A-Cchr13-110307296-A-Gchr13-110307296-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):c.-277A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 371,128 control chromosomes in the GnomAD database, including 70,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30465 hom., cov: 33)
  • Exomes 𝑓: 0.60 (39598 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 13-110307296-A-C is Benign according to our data. Variant chr13-110307296-A-C is described in ClinVar as [Benign]. Clinvar id is 311089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.-277A>C		5_prime_UTR_variant	1/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.-277A>C		5_prime_UTR_variant	1/48	5	NM_001846.4	P1
COL4A2	ENST00000649101.1	c.-277A>C		5_prime_UTR_variant	1/4
COL4A2	ENST00000400163.7	c.-44-564A>C		intron_variant		5
COL4A2	ENST00000480771.5	n.30A>C		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95586 AN: 151560 Hom.: 30414 Cov.: 33

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.600 AC: 131757 AN: 219460 Hom.: 39598 Cov.: 1 AF XY: 0.601 AC XY: 67483 AN XY: 112256

Gnomad4 AFR exome AF: 0.702

Gnomad4 AMR exome AF: 0.700

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.617

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.600

GnomAD4 genome AF: 0.631 AC: 95693 AN: 151668 Hom.: 30465 Cov.: 33 AF XY: 0.634 AC XY: 47006 AN XY: 74122

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.587

Gnomad4 OTH AF: 0.624

Alfa AF: 0.514 Hom.: 1488

Bravo AF: 0.636

Asia WGS AF: 0.557 AC: 1913 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Porencephaly 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Porencephalic cyst Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	3.4
Dann	Benign	0.42

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: rs7989823; hg19: chr13-110959643;