rs422733

Positions:

• chr13-110512267-T-C
• chr13-110512267-T-G

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.*76T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,477,380 control chromosomes in the GnomAD database, including 234,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (22951 hom., cov: 31)
  • Exomes 𝑓: 0.56 (211488 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900

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=-0.84).
• BP6: Variant 13-110512267-T-C is Benign according to our data. Variant chr13-110512267-T-C is described in ClinVar as [Benign]. Clinvar id is 311200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.*76T>C		3_prime_UTR_variant	48/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.*76T>C		3_prime_UTR_variant	48/48	5	NM_001846.4	P1
COL4A2	ENST00000648222.1	n.903T>C		non_coding_transcript_exon_variant	1/1
COL4A2	ENST00000650225.1	n.2870T>C		non_coding_transcript_exon_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.548 AC: 82884 AN: 151262 Hom.: 22930 Cov.: 31

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.570

GnomAD4 exome AF: 0.561 AC: 744244 AN: 1326000 Hom.: 211488 Cov.: 32 AF XY: 0.559 AC XY: 362572 AN XY: 649038

Gnomad4 AFR exome AF: 0.562

Gnomad4 AMR exome AF: 0.560

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.470

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.580

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.548 AC: 82951 AN: 151380 Hom.: 22951 Cov.: 31 AF XY: 0.541 AC XY: 39998 AN XY: 73954

Gnomad4 AFR AF: 0.562

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.575

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.564

Alfa AF: 0.569 Hom.: 9069

Bravo AF: 0.556

Asia WGS AF: 0.418 AC: 1454 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2019	- -

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	5.1
DANN	Benign	0.65

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: rs422733; hg19: chr13-111164614;