rs2281974

Positions:

• chr13-110478172-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.2587+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,569,294 control chromosomes in the GnomAD database, including 95,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12597 hom., cov: 33)
  • Exomes 𝑓: 0.34 (83099 hom.)
• Consequence: COL4A2 NM_001846.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004793
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.906

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=-0.92).
• BP6: Variant 13-110478172-C-T is Benign according to our data. Variant chr13-110478172-C-T is described in ClinVar as [Benign]. Clinvar id is 311150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110478172-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.2587+8C>T		splice_region_variant, intron_variant		ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.2587+8C>T		splice_region_variant, intron_variant		5	NM_001846.4	P1
COL4A2	ENST00000483683.2	n.217+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		2
COL4A2	ENST00000650225.1	n.242+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59472 AN: 151924 Hom.: 12570 Cov.: 33

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.375 AC: 78780 AN: 209908 Hom.: 15007 AF XY: 0.375 AC XY: 43290 AN XY: 115402

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.492

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.337 AC: 477944 AN: 1417252 Hom.: 83099 Cov.: 33 AF XY: 0.341 AC XY: 239539 AN XY: 702380

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.370

Gnomad4 ASJ exome AF: 0.372

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.487

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.392 AC: 59562 AN: 152042 Hom.: 12597 Cov.: 33 AF XY: 0.391 AC XY: 29062 AN XY: 74316

Gnomad4 AFR AF: 0.547

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.367

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.390

Alfa AF: 0.359 Hom.: 4990

Bravo AF: 0.399

Asia WGS AF: 0.490 AC: 1707 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.92
CADD	Benign	0.88
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0
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: rs2281974; hg19: chr13-111130519; COSMIC: COSV64629954; COSMIC: COSV64629954;