chr13-110512841-T-C

Variant names:

• chr13-110512841-T-C
• rs1049977
• NM_001846.4:c.*650T>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.*650T>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 0.404 in 151,832 control chromosomes in the GnomAD database, including 12,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12695 hom., cov: 32)
  • Exomes 𝑓: 0.53 (48 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: 0.624
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 13-110512841-T-C is Benign according to our data. Variant chr13-110512841-T-C is described in ClinVar as Benign. ClinVar VariationId is 311211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*650T>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.*650T>C		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61325 AN: 151714 Hom.: 12696 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.405

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.533 AC: 162 AN: 304 Hom.: 48 Cov.: 0 AF XY: 0.541 AC XY: 93 AN XY: 172

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.375 AC: 3 AN: 8

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.500 AC: 9 AN: 18

European-Finnish (FIN) AF: 0.500 AC: 7 AN: 14

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.547 AC: 127 AN: 232

Other (OTH) AF: 0.545 AC: 12 AN: 22

GnomAD4 genome AF: 0.404 AC: 61344 AN: 151832 Hom.: 12695 Cov.: 32 AF XY: 0.402 AC XY: 29790 AN XY: 74170

African (AFR) AF: 0.320 AC: 13266 AN: 41434

American (AMR) AF: 0.446 AC: 6804 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1004 AN: 5166

South Asian (SAS) AF: 0.380 AC: 1831 AN: 4818

European-Finnish (FIN) AF: 0.418 AC: 4398 AN: 10534

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.461 AC: 31295 AN: 67834

Other (OTH) AF: 0.400 AC: 845 AN: 2112

Alfa AF: 0.442 Hom.: 52530

Bravo AF: 0.403

Asia WGS AF: 0.335 AC: 1168 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	3.8
DANN	Benign	0.54
PhyloP100		0.62
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: rs1049977; hg19: chr13-111165188;