rs34734302

Variant names:

• chr13-110449836-A-G
• rs34734302
• NM_001846.4:c.1189+47A>G

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.1189+47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,522,806 control chromosomes in the GnomAD database, including 182,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16684 hom., cov: 32)
  • Exomes 𝑓: 0.49 (166108 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.67
• Publications: 8 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=-0.95).
• BP6: Variant 13-110449836-A-G is Benign according to our data. Variant chr13-110449836-A-G is described in ClinVar as [Benign]. Clinvar id is 1249478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1189+47A>G		intron_variant	Intron 19 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1189+47A>G		intron_variant	Intron 19 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70720 AN: 151796 Hom.: 16662 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.452 AC: 62855 AN: 139184 AF XY: 0.457

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.317

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.499

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.489 AC: 670917 AN: 1370892 Hom.: 166108 Cov.: 24 AF XY: 0.490 AC XY: 331798 AN XY: 677174

African (AFR) AF: 0.446 AC: 13684 AN: 30680

American (AMR) AF: 0.350 AC: 11448 AN: 32730

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 8710 AN: 24730

East Asian (EAS) AF: 0.322 AC: 11469 AN: 35566

South Asian (SAS) AF: 0.488 AC: 37771 AN: 77398

European-Finnish (FIN) AF: 0.534 AC: 23449 AN: 43916

Middle Eastern (MID) AF: 0.368 AC: 1480 AN: 4018

European-Non Finnish (NFE) AF: 0.504 AC: 536347 AN: 1064844

Other (OTH) AF: 0.466 AC: 26559 AN: 57010

GnomAD4 genome AF: 0.466 AC: 70766 AN: 151914 Hom.: 16684 Cov.: 32 AF XY: 0.467 AC XY: 34675 AN XY: 74264

African (AFR) AF: 0.449 AC: 18580 AN: 41426

American (AMR) AF: 0.384 AC: 5872 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1292 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1645 AN: 5140

South Asian (SAS) AF: 0.491 AC: 2365 AN: 4816

European-Finnish (FIN) AF: 0.526 AC: 5549 AN: 10550

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 33953 AN: 67912

Other (OTH) AF: 0.427 AC: 901 AN: 2110

Alfa AF: 0.468 Hom.: 3376

Bravo AF: 0.447

Asia WGS AF: 0.406 AC: 1417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.040
DANN	Benign	0.16
PhyloP100		-5.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs34734302; hg19: chr13-111102183; COSMIC: COSV64633815;