rs3803236

Variant names:

• chr13-110465398-C-T
• rs3803236
• NM_001846.4:c.1777-7C>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.1777-7C>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 0.578 in 1,578,806 control chromosomes in the GnomAD database, including 268,757 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 0.58 (26270 hom., cov: 34)
  • Exomes 𝑓: 0.58 (242487 hom.)
• Consequence: COL4A2 NM_001846.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002156
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0860
• Publications: 18 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=-0.81).
• BP6: Variant 13-110465398-C-T is Benign according to our data. Variant chr13-110465398-C-T is described in ClinVar as Benign. ClinVar VariationId is 311134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1777-7C>T		splice_region_variant, intron_variant	Intron 24 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1777-7C>T		splice_region_variant, intron_variant	Intron 24 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88134 AN: 152050 Hom.: 26246 Cov.: 34

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.589

GnomAD2 exomes AF: 0.530 AC: 113043 AN: 213246 AF XY: 0.533

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.577 AC: 823741 AN: 1426638 Hom.: 242487 Cov.: 44 AF XY: 0.575 AC XY: 407868 AN XY: 709134

African (AFR) AF: 0.665 AC: 20750 AN: 31194

American (AMR) AF: 0.418 AC: 14018 AN: 33518

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 15488 AN: 23816

East Asian (EAS) AF: 0.258 AC: 10209 AN: 39514

South Asian (SAS) AF: 0.478 AC: 38611 AN: 80720

European-Finnish (FIN) AF: 0.444 AC: 22968 AN: 51708

Middle Eastern (MID) AF: 0.663 AC: 3447 AN: 5198

European-Non Finnish (NFE) AF: 0.603 AC: 664388 AN: 1102300

Other (OTH) AF: 0.577 AC: 33862 AN: 58670

GnomAD4 genome AF: 0.580 AC: 88214 AN: 152168 Hom.: 26270 Cov.: 34 AF XY: 0.567 AC XY: 42183 AN XY: 74398

African (AFR) AF: 0.653 AC: 27096 AN: 41516

American (AMR) AF: 0.499 AC: 7632 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2328 AN: 3470

East Asian (EAS) AF: 0.292 AC: 1510 AN: 5170

South Asian (SAS) AF: 0.462 AC: 2231 AN: 4830

European-Finnish (FIN) AF: 0.429 AC: 4541 AN: 10586

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40802 AN: 67980

Other (OTH) AF: 0.589 AC: 1245 AN: 2114

Alfa AF: 0.603 Hom.: 51140

Bravo AF: 0.587

Asia WGS AF: 0.402 AC: 1400 AN: 3478

EpiCase AF: 0.604

EpiControl AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 10, 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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 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	-0.81
CADD	Benign	6.9
DANN	Benign	0.69
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0020
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: rs3803236; hg19: chr13-111117745; COSMIC: COSV64626293; COSMIC: COSV64626293;