13-110512918-G-C

Variant names:

• chr13-110512918-G-C
• rs15457
• NM_001846.4:c.*727G>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.*727G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,878 control chromosomes in the GnomAD database, including 15,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15098 hom., cov: 31)
  • Exomes 𝑓: 0.46 (6 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-110512918-G-C is Benign according to our data. Variant chr13-110512918-G-C is described in ClinVar as Benign. ClinVar VariationId is 311214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*727G>C		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.*727G>C		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66823 AN: 151706 Hom.: 15090 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.431

GnomAD4 exome AF: 0.463 AC: 25 AN: 54 Hom.: 6 Cov.: 0 AF XY: 0.475 AC XY: 19 AN XY: 40

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.750 AC: 3 AN: 4

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.344 AC: 11 AN: 32

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.440 AC: 66865 AN: 151824 Hom.: 15098 Cov.: 31 AF XY: 0.448 AC XY: 33195 AN XY: 74172

African (AFR) AF: 0.351 AC: 14544 AN: 41380

American (AMR) AF: 0.431 AC: 6575 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1493 AN: 3468

East Asian (EAS) AF: 0.753 AC: 3878 AN: 5152

South Asian (SAS) AF: 0.557 AC: 2684 AN: 4816

European-Finnish (FIN) AF: 0.532 AC: 5596 AN: 10510

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30579 AN: 67924

Other (OTH) AF: 0.437 AC: 924 AN: 2114

Alfa AF: 0.314 Hom.: 866

Bravo AF: 0.429

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

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	-0.90
CADD	Benign	1.4
DANN	Benign	0.43
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs15457; hg19: chr13-111165265;