rs1049931

Positions:

• chr13-110512748-A-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.*557A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 155,224 control chromosomes in the GnomAD database, including 13,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12890 hom., cov: 33)
  • Exomes 𝑓: 0.48 (369 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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=-0.88).
• BP6: Variant 13-110512748-A-G is Benign according to our data. Variant chr13-110512748-A-G is described in ClinVar as [Benign]. Clinvar id is 311209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*557A>G		3_prime_UTR_variant	48/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.*557A>G		3_prime_UTR_variant	48/48	5	NM_001846.4	ENSP00000353654	P1
COL4A2	ENST00000648222.1	n.1384A>G		non_coding_transcript_exon_variant	1/1
COL4A2	ENST00000650225.1	n.3351A>G		non_coding_transcript_exon_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61777 AN: 152064 Hom.: 12891 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.481 AC: 1464 AN: 3042 Hom.: 369 Cov.: 0 AF XY: 0.475 AC XY: 717 AN XY: 1510

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.525

GnomAD4 genome AF: 0.406 AC: 61798 AN: 152182 Hom.: 12890 Cov.: 33 AF XY: 0.404 AC XY: 30047 AN XY: 74400

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.402

Alfa AF: 0.449 Hom.: 14737

Bravo AF: 0.404

Asia WGS AF: 0.337 AC: 1174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1049931; hg19: chr13-111165095;