rs2281974

Variant names:

• chr13-110478172-C-T
• rs2281974
• NM_001846.4:c.2587+8C>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.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
• Publications: 13 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=-0.92).
• BP6: Variant 13-110478172-C-T is Benign according to our data. Variant chr13-110478172-C-T is described in ClinVar as Benign. ClinVar VariationId is 311150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.2587+8C>T		splice_region intron	N/A	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.2587+8C>T		splice_region intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.2668+8C>T		splice_region intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.2587+8C>T		splice_region intron	N/A	ENSP00000383027.4

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

GnomAD2 exomes AF: 0.375 AC: 78780 AN: 209908 AF XY: 0.375

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 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

African (AFR) AF: 0.550 AC: 17664 AN: 32094

American (AMR) AF: 0.370 AC: 14542 AN: 39268

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 9121 AN: 24504

East Asian (EAS) AF: 0.467 AC: 17918 AN: 38344

South Asian (SAS) AF: 0.487 AC: 39321 AN: 80782

European-Finnish (FIN) AF: 0.294 AC: 15068 AN: 51216

Middle Eastern (MID) AF: 0.322 AC: 1395 AN: 4336

European-Non Finnish (NFE) AF: 0.314 AC: 341720 AN: 1088532

Other (OTH) AF: 0.364 AC: 21195 AN: 58176

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

African (AFR) AF: 0.547 AC: 22680 AN: 41480

American (AMR) AF: 0.351 AC: 5359 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1272 AN: 3470

East Asian (EAS) AF: 0.469 AC: 2409 AN: 5136

South Asian (SAS) AF: 0.502 AC: 2420 AN: 4820

European-Finnish (FIN) AF: 0.296 AC: 3132 AN: 10588

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.312 AC: 21198 AN: 67948

Other (OTH) AF: 0.390 AC: 825 AN: 2116

Alfa AF: 0.356 Hom.: 6303

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.38
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2281974; hg19: chr13-111130519; COSMIC: COSV64629954; COSMIC: COSV64629954;