13-110512608-C-G

Variant names:

• chr13-110512608-C-G
• rs10509
• NM_001846.4:c.*417C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001846.4(COL4A2):​c.*417C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 180,346 control chromosomes in the GnomAD database, including 70,520 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (58859 hom., cov: 33)
  • Exomes 𝑓: 0.91 (11661 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.07
• Publications: 10 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

ENSG00000289010 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*417C>G		3_prime_UTR_variant	Exon 48 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.*417C>G		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133482 AN: 152116 Hom.: 58820 Cov.: 33

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.910 AC: 25587 AN: 28112 Hom.: 11661 Cov.: 0 AF XY: 0.913 AC XY: 13064 AN XY: 14314

African (AFR) AF: 0.785 AC: 408 AN: 520

American (AMR) AF: 0.896 AC: 1281 AN: 1430

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 637 AN: 766

East Asian (EAS) AF: 0.933 AC: 569 AN: 610

South Asian (SAS) AF: 0.935 AC: 2484 AN: 2658

European-Finnish (FIN) AF: 0.947 AC: 1203 AN: 1270

Middle Eastern (MID) AF: 0.858 AC: 103 AN: 120

European-Non Finnish (NFE) AF: 0.913 AC: 17315 AN: 18964

Other (OTH) AF: 0.895 AC: 1587 AN: 1774

GnomAD4 genome AF: 0.877 AC: 133581 AN: 152234 Hom.: 58859 Cov.: 33 AF XY: 0.883 AC XY: 65695 AN XY: 74438

African (AFR) AF: 0.783 AC: 32479 AN: 41486

American (AMR) AF: 0.889 AC: 13596 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2886 AN: 3472

East Asian (EAS) AF: 0.947 AC: 4901 AN: 5178

South Asian (SAS) AF: 0.953 AC: 4601 AN: 4828

European-Finnish (FIN) AF: 0.954 AC: 10121 AN: 10610

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 62025 AN: 68036

Other (OTH) AF: 0.861 AC: 1821 AN: 2116

Alfa AF: 0.894 Hom.: 2972

Bravo AF: 0.867

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porencephaly 2 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.40
DANN	Benign	0.48
PhyloP100		-4.1
Mutation Taster		=99/1	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: rs10509; hg19: chr13-111164955;