rs3803228

Variant names:

• chr13-110482511-T-C
• rs3803228
• NM_001846.4:c.2759-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.2759-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,612,576 control chromosomes in the GnomAD database, including 27,049 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 0.19 (2742 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24307 hom.)
• Consequence: COL4A2 NM_001846.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001324
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.445
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-110482511-T-C is Benign according to our data. Variant chr13-110482511-T-C is described in ClinVar as Benign. ClinVar VariationId is 311152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2759-5T>C		splice_region_variant, intron_variant	Intron 31 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2759-5T>C		splice_region_variant, intron_variant	Intron 31 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28532 AN: 152070 Hom.: 2743 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.172 AC: 43032 AN: 249480 AF XY: 0.173

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.180 AC: 262650 AN: 1460388 Hom.: 24307 Cov.: 32 AF XY: 0.179 AC XY: 130293 AN XY: 726400

African (AFR) AF: 0.238 AC: 7968 AN: 33446

American (AMR) AF: 0.127 AC: 5664 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3316 AN: 26128

East Asian (EAS) AF: 0.176 AC: 6998 AN: 39666

South Asian (SAS) AF: 0.192 AC: 16560 AN: 86216

European-Finnish (FIN) AF: 0.138 AC: 7377 AN: 53400

Middle Eastern (MID) AF: 0.112 AC: 643 AN: 5766

European-Non Finnish (NFE) AF: 0.183 AC: 203413 AN: 1110728

Other (OTH) AF: 0.177 AC: 10711 AN: 60346

GnomAD4 genome AF: 0.188 AC: 28541 AN: 152188 Hom.: 2742 Cov.: 32 AF XY: 0.186 AC XY: 13822 AN XY: 74422

African (AFR) AF: 0.231 AC: 9589 AN: 41500

American (AMR) AF: 0.146 AC: 2238 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3468

East Asian (EAS) AF: 0.199 AC: 1031 AN: 5172

South Asian (SAS) AF: 0.195 AC: 941 AN: 4832

European-Finnish (FIN) AF: 0.132 AC: 1403 AN: 10612

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12171 AN: 67998

Other (OTH) AF: 0.167 AC: 352 AN: 2110

Alfa AF: 0.182 Hom.: 7232

Bravo AF: 0.191

Asia WGS AF: 0.198 AC: 691 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Porencephaly 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.71
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3803228; hg19: chr13-111134858; COSMIC: COSV64624934;