rs9301457

Variant names:

• chr13-110478252-G-C
• rs9301457
• NM_001846.4:c.2587+88G>C

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+88G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 1,338,538 control chromosomes in the GnomAD database, including 447,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50365 hom., cov: 32)
  • Exomes 𝑓: 0.82 (397426 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.152
• Publications: 4 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=-1.01).
• BP6: Variant 13-110478252-G-C is Benign according to our data. Variant chr13-110478252-G-C is described in ClinVar as Benign. ClinVar VariationId is 1232864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2587+88G>C		intron_variant	Intron 30 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2587+88G>C		intron_variant	Intron 30 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123628 AN: 152104 Hom.: 50315 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.857

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.834

GnomAD4 exome AF: 0.818 AC: 970309 AN: 1186316 Hom.: 397426 AF XY: 0.820 AC XY: 472347 AN XY: 575778

African (AFR) AF: 0.766 AC: 19688 AN: 25708

American (AMR) AF: 0.866 AC: 15156 AN: 17506

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 15390 AN: 17698

East Asian (EAS) AF: 0.882 AC: 28258 AN: 32028

South Asian (SAS) AF: 0.874 AC: 47786 AN: 54654

European-Finnish (FIN) AF: 0.848 AC: 36474 AN: 43026

Middle Eastern (MID) AF: 0.885 AC: 2936 AN: 3316

European-Non Finnish (NFE) AF: 0.810 AC: 764061 AN: 943442

Other (OTH) AF: 0.829 AC: 40560 AN: 48938

GnomAD4 genome AF: 0.813 AC: 123739 AN: 152222 Hom.: 50365 Cov.: 32 AF XY: 0.816 AC XY: 60714 AN XY: 74420

African (AFR) AF: 0.774 AC: 32146 AN: 41538

American (AMR) AF: 0.852 AC: 13035 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 2973 AN: 3468

East Asian (EAS) AF: 0.840 AC: 4333 AN: 5158

South Asian (SAS) AF: 0.871 AC: 4201 AN: 4822

European-Finnish (FIN) AF: 0.854 AC: 9067 AN: 10614

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.814 AC: 55334 AN: 68008

Other (OTH) AF: 0.837 AC: 1769 AN: 2114

Alfa AF: 0.809 Hom.: 5449

Bravo AF: 0.808

Asia WGS AF: 0.860 AC: 2992 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	-1.0
CADD	Benign	3.4
DANN	Benign	0.34
PhyloP100		-0.15
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: rs9301457; hg19: chr13-111130599;