chr13-110492065-C-G

Variant names:

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

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=-0.8).
• BP6: Variant 13-110492065-C-G is Benign according to our data. Variant chr13-110492065-C-G is described in ClinVar as [Benign]. Clinvar id is 311163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110492065-C-G is described in Lovd as [Benign].
• 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
COL4A2	ENST00000650225.1	n.1110-5C>G		splice_region_variant, intron_variant	Intron 8 of 18

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

GnomAD3 exomes AF: 0.0940 AC: 14459 AN: 153768 Hom.: 963 AF XY: 0.101 AC XY: 8207 AN XY: 81408

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 SAS exome AF: 0.188

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

Gnomad4 AFR exome AF: 0.0327

Gnomad4 AMR exome AF: 0.0575

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.0482

Gnomad4 OTH exome AF: 0.0751

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

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.0686

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.0528

Gnomad4 OTH AF: 0.0620

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

-

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2296849; hg19: chr13-111144412; COSMIC: COSV64630525;