rs388222

Variant names:

• chr13-110501812-C-T
• rs388222
• NM_001846.4:c.3877+28C>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.3877+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,602,492 control chromosomes in the GnomAD database, including 126,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11610 hom., cov: 31)
  • Exomes 𝑓: 0.39 (114995 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 11 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=-0.91).
• BP6: Variant 13-110501812-C-T is Benign according to our data. Variant chr13-110501812-C-T is described in ClinVar as [Benign]. Clinvar id is 1243167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.3877+28C>T		intron_variant	Intron 41 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.3877+28C>T		intron_variant	Intron 41 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58381 AN: 151782 Hom.: 11596 Cov.: 31

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.418 AC: 101692 AN: 243312 AF XY: 0.409

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.577

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.641

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.392 AC: 569018 AN: 1450594 Hom.: 114995 Cov.: 29 AF XY: 0.391 AC XY: 282098 AN XY: 722078

African (AFR) AF: 0.319 AC: 10548 AN: 33042

American (AMR) AF: 0.561 AC: 24428 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 10625 AN: 25982

East Asian (EAS) AF: 0.688 AC: 27256 AN: 39600

South Asian (SAS) AF: 0.369 AC: 31451 AN: 85316

European-Finnish (FIN) AF: 0.333 AC: 17707 AN: 53130

Middle Eastern (MID) AF: 0.317 AC: 1820 AN: 5734

European-Non Finnish (NFE) AF: 0.382 AC: 421698 AN: 1104232

Other (OTH) AF: 0.391 AC: 23485 AN: 59988

GnomAD4 genome AF: 0.385 AC: 58436 AN: 151898 Hom.: 11610 Cov.: 31 AF XY: 0.386 AC XY: 28686 AN XY: 74234

African (AFR) AF: 0.330 AC: 13666 AN: 41438

American (AMR) AF: 0.477 AC: 7280 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3470

East Asian (EAS) AF: 0.649 AC: 3336 AN: 5142

South Asian (SAS) AF: 0.366 AC: 1758 AN: 4802

European-Finnish (FIN) AF: 0.341 AC: 3598 AN: 10560

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26077 AN: 67912

Other (OTH) AF: 0.388 AC: 816 AN: 2104

Alfa AF: 0.384 Hom.: 2322

Bravo AF: 0.398

Asia WGS AF: 0.462 AC: 1605 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.48
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs388222; hg19: chr13-111154159; COSMIC: COSV107471777; COSMIC: COSV107471777;