13-110480209-C-T

Variant names:

• chr13-110480209-C-T
• rs9521803
• NM_001846.4:c.2588-11C>T

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.2588-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,581,508 control chromosomes in the GnomAD database, including 74,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6061 hom., cov: 34)
  • Exomes 𝑓: 0.31 (68332 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Scores: Splicing: ADA: 0.00004166
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.08
• Publications: 9 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=-0.87).
• BP6: Variant 13-110480209-C-T is Benign according to our data. Variant chr13-110480209-C-T is described in ClinVar as Benign. ClinVar VariationId is 311151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2588-11C>T		intron_variant	Intron 30 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2588-11C>T		intron_variant	Intron 30 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39575 AN: 152078 Hom.: 6053 Cov.: 34

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.308 AC: 68886 AN: 223460 AF XY: 0.309

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.323

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.306 AC: 436893 AN: 1429312 Hom.: 68332 Cov.: 33 AF XY: 0.305 AC XY: 216954 AN XY: 710270

African (AFR) AF: 0.0683 AC: 2174 AN: 31836

American (AMR) AF: 0.371 AC: 13953 AN: 37650

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 7655 AN: 24316

East Asian (EAS) AF: 0.377 AC: 14706 AN: 38974

South Asian (SAS) AF: 0.290 AC: 23576 AN: 81352

European-Finnish (FIN) AF: 0.381 AC: 20103 AN: 52716

Middle Eastern (MID) AF: 0.307 AC: 1571 AN: 5114

European-Non Finnish (NFE) AF: 0.306 AC: 336072 AN: 1098498

Other (OTH) AF: 0.290 AC: 17083 AN: 58856

GnomAD4 genome AF: 0.260 AC: 39589 AN: 152196 Hom.: 6061 Cov.: 34 AF XY: 0.266 AC XY: 19804 AN XY: 74392

African (AFR) AF: 0.0850 AC: 3533 AN: 41566

American (AMR) AF: 0.351 AC: 5369 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1078 AN: 3464

East Asian (EAS) AF: 0.337 AC: 1740 AN: 5170

South Asian (SAS) AF: 0.281 AC: 1356 AN: 4824

European-Finnish (FIN) AF: 0.390 AC: 4125 AN: 10586

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21431 AN: 67976

Other (OTH) AF: 0.282 AC: 595 AN: 2110

Alfa AF: 0.291 Hom.: 18101

Bravo AF: 0.247

Asia WGS AF: 0.295 AC: 1024 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 02, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Porencephaly 2 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.87
CADD	Benign	5.6
DANN	Benign	0.24
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
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

Other links and lift over

dbSNP: rs9521803; hg19: chr13-111132556; COSMIC: COSV64626324;