rs2296849

Variant names:

• chr13-110492065-C-G
• rs2296849
• NM_001846.4:c.3455-5C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110492065-C-G
• chr13-110492065-C-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.3455-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 1,551,114 control chromosomes in the GnomAD database, including 5,088 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 0.066 (486 hom., cov: 33)
  • Exomes 𝑓: 0.066 (4602 hom.)
• Consequence: COL4A2 NM_001846.4 splice_region, intron
• Scores: Splicing: ADA: 0.005272
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.25
• Publications: 11 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=-0.8).
• BP6: Variant 13-110492065-C-G is Benign according to our data. Variant chr13-110492065-C-G is described in ClinVar as Benign. ClinVar VariationId is 311163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.3455-5C>G		splice_region_variant, intron_variant	Intron 37 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.3455-5C>G		splice_region_variant, intron_variant	Intron 37 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10039 AN: 152160 Hom.: 487 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0528

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0940 AC: 14459 AN: 153768 AF XY: 0.101

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0659 AC: 92184 AN: 1398836 Hom.: 4602 Cov.: 31 AF XY: 0.0698 AC XY: 48126 AN XY: 689944

African (AFR) AF: 0.0327 AC: 1033 AN: 31590

American (AMR) AF: 0.0575 AC: 2051 AN: 35640

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2951 AN: 25140

East Asian (EAS) AF: 0.189 AC: 6760 AN: 35736

South Asian (SAS) AF: 0.188 AC: 14916 AN: 79172

European-Finnish (FIN) AF: 0.154 AC: 7560 AN: 49170

Middle Eastern (MID) AF: 0.0903 AC: 514 AN: 5690

European-Non Finnish (NFE) AF: 0.0482 AC: 52043 AN: 1078706

Other (OTH) AF: 0.0751 AC: 4356 AN: 57992

GnomAD4 genome AF: 0.0660 AC: 10046 AN: 152278 Hom.: 486 Cov.: 33 AF XY: 0.0734 AC XY: 5466 AN XY: 74454

African (AFR) AF: 0.0306 AC: 1272 AN: 41576

American (AMR) AF: 0.0686 AC: 1050 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.174 AC: 897 AN: 5166

South Asian (SAS) AF: 0.198 AC: 955 AN: 4820

European-Finnish (FIN) AF: 0.159 AC: 1691 AN: 10614

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0528 AC: 3589 AN: 68008

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

Alfa AF: 0.0607 Hom.: 129

Bravo AF: 0.0525

Asia WGS AF: 0.158 AC: 548 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 02, 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

- -

Jun 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. -

Porencephaly 2 Benign:1

Jan 13, 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	-0.80
CADD	Benign	8.1
DANN	Benign	0.32
PhyloP100		1.2
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0053
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.090		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: rs2296849; hg19: chr13-111144412; COSMIC: COSV64630525;