chr13-110512732-C-T

Variant names:

• chr13-110512732-C-T
• rs1049906
• NM_001846.4:c.*541C>T

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.*541C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 155,600 control chromosomes in the GnomAD database, including 15,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14862 hom., cov: 33)
  • Exomes 𝑓: 0.34 (193 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 13 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=-0.99).
• BP6: Variant 13-110512732-C-T is Benign according to our data. Variant chr13-110512732-C-T is described in ClinVar as Benign. ClinVar VariationId is 311208.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.*541C>T		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.*541C>T		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66180 AN: 152034 Hom.: 14853 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.429

GnomAD4 exome AF: 0.340 AC: 1171 AN: 3448 Hom.: 193 Cov.: 0 AF XY: 0.347 AC XY: 574 AN XY: 1656

African (AFR) AF: 0.238 AC: 10 AN: 42

American (AMR) AF: 0.323 AC: 100 AN: 310

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 7 AN: 36

East Asian (EAS) AF: 0.313 AC: 5 AN: 16

South Asian (SAS) AF: 0.447 AC: 76 AN: 170

European-Finnish (FIN) AF: 0.449 AC: 44 AN: 98

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.334 AC: 854 AN: 2556

Other (OTH) AF: 0.344 AC: 75 AN: 218

GnomAD4 genome AF: 0.435 AC: 66221 AN: 152152 Hom.: 14862 Cov.: 33 AF XY: 0.443 AC XY: 32974 AN XY: 74376

African (AFR) AF: 0.335 AC: 13888 AN: 41504

American (AMR) AF: 0.427 AC: 6533 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3472

East Asian (EAS) AF: 0.753 AC: 3898 AN: 5178

South Asian (SAS) AF: 0.572 AC: 2760 AN: 4822

European-Finnish (FIN) AF: 0.533 AC: 5647 AN: 10592

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30489 AN: 67984

Other (OTH) AF: 0.436 AC: 921 AN: 2114

Alfa AF: 0.440 Hom.: 45054

Bravo AF: 0.423

Asia WGS AF: 0.583 AC: 2022 AN: 3478

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	-0.99
CADD	Benign	0.20
DANN	Benign	0.59
PhyloP100		-1.0
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: rs1049906; hg19: chr13-111165079;