rs7990009

Positions:

• chr13-110307341-C-G
• chr13-110307341-C-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.-232C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 293,478 control chromosomes in the GnomAD database, including 14,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7473 hom., cov: 33)
  • Exomes 𝑓: 0.30 (6665 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.145

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]

COL4A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-110307341-C-G is Benign according to our data. Variant chr13-110307341-C-G is described in ClinVar as [Benign]. Clinvar id is 311090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.-232C>G		5_prime_UTR_premature_start_codon_gain_variant	1/48	ENST00000360467.7	NP_001837.2
COL4A2	NM_001846.4	c.-232C>G		5_prime_UTR_variant	1/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467	c.-232C>G		5_prime_UTR_premature_start_codon_gain_variant	1/48	5	NM_001846.4	ENSP00000353654.5
COL4A2	ENST00000360467	c.-232C>G		5_prime_UTR_variant	1/48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47078 AN: 151682 Hom.: 7450 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.300 AC: 42513 AN: 141688 Hom.: 6665 Cov.: 0 AF XY: 0.301 AC XY: 21514 AN XY: 71366

Gnomad4 AFR exome AF: 0.327

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.311 AC: 47140 AN: 151790 Hom.: 7473 Cov.: 33 AF XY: 0.314 AC XY: 23299 AN XY: 74166

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.266

Alfa AF: 0.205 Hom.: 511

Bravo AF: 0.307

Asia WGS AF: 0.298 AC: 1028 AN: 3446

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	May 20, 2021	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.6
DANN	Benign	0.63

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: rs7990009; hg19: chr13-110959688; COSMIC: COSV64625842; COSMIC: COSV64625842;