rs7711

Variant names:

• chr13-110512854-T-C
• rs7711
• NM_001846.4:c.*663T>C

Variant summary

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

The NM_001846.4(COL4A2):​c.*663T>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 0.437 in 151,786 control chromosomes in the GnomAD database, including 14,610 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 0.44 (14610 hom., cov: 32)
  • Exomes 𝑓: 0.52 (24 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*663T>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.*663T>C		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66308 AN: 151668 Hom.: 14601 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.426

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.520 AC: 79 AN: 152 Hom.: 24 Cov.: 0 AF XY: 0.489 AC XY: 46 AN XY: 94

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.667 AC: 4 AN: 6

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 5 AN: 10

European-Finnish (FIN) AF: 0.500 AC: 5 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.518 AC: 57 AN: 110

Other (OTH) AF: 0.571 AC: 8 AN: 14

GnomAD4 genome AF: 0.437 AC: 66355 AN: 151786 Hom.: 14610 Cov.: 32 AF XY: 0.434 AC XY: 32199 AN XY: 74152

African (AFR) AF: 0.433 AC: 17924 AN: 41418

American (AMR) AF: 0.459 AC: 6997 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1401 AN: 3464

East Asian (EAS) AF: 0.195 AC: 1007 AN: 5160

South Asian (SAS) AF: 0.381 AC: 1834 AN: 4814

European-Finnish (FIN) AF: 0.418 AC: 4404 AN: 10534

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.462 AC: 31347 AN: 67834

Other (OTH) AF: 0.421 AC: 886 AN: 2106

Alfa AF: 0.448 Hom.: 5747

Bravo AF: 0.440

Asia WGS AF: 0.346 AC: 1208 AN: 3478

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	-0.89
CADD	Benign	0.44
DANN	Benign	0.49
PhyloP100		-1.3
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: rs7711; hg19: chr13-111165201;