rs2296853

Positions:

• chr13-110484893-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.2903-12A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,601,718 control chromosomes in the GnomAD database, including 22,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1872 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20418 hom.)
• Consequence: COL4A2 NM_001846.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002152
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.147

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=-0.82).
• BP6: Variant 13-110484893-A-G is Benign according to our data. Variant chr13-110484893-A-G is described in ClinVar as [Benign]. Clinvar id is 311153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110484893-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2903-12A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2903-12A>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001846.4	ENSP00000353654	P1
COL4A2	ENST00000650225.1	n.558-12A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21181 AN: 151796 Hom.: 1868 Cov.: 31

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0980

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.159 AC: 38469 AN: 242686 Hom.: 3414 AF XY: 0.156 AC XY: 20523 AN XY: 131956

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.0965

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.163 AC: 236686 AN: 1449800 Hom.: 20418 Cov.: 33 AF XY: 0.161 AC XY: 116103 AN XY: 720514

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.139 AC: 21188 AN: 151918 Hom.: 1872 Cov.: 31 AF XY: 0.141 AC XY: 10468 AN XY: 74264

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0985

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.154

Alfa AF: 0.158 Hom.: 515

Bravo AF: 0.140

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
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: rs2296853; hg19: chr13-111137240;