13-110482433-G-A

Variant names:

• chr13-110482433-G-A
• rs3803229
• NM_001846.4:c.2759-83G>A

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.2759-83G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,463,490 control chromosomes in the GnomAD database, including 75,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6638 hom., cov: 34)
  • Exomes 𝑓: 0.32 (69290 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.127
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-110482433-G-A is Benign according to our data. Variant chr13-110482433-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.2759-83G>A		intron	N/A	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.2759-83G>A		intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.2840-83G>A		intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.2759-83G>A		intron	N/A	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42694 AN: 152094 Hom.: 6631 Cov.: 34

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.323 AC: 422961 AN: 1311278 Hom.: 69290 AF XY: 0.323 AC XY: 210354 AN XY: 652108

African (AFR) AF: 0.130 AC: 3808 AN: 29246

American (AMR) AF: 0.402 AC: 15575 AN: 38702

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 6835 AN: 23544

East Asian (EAS) AF: 0.413 AC: 15810 AN: 38312

South Asian (SAS) AF: 0.327 AC: 25891 AN: 79096

European-Finnish (FIN) AF: 0.406 AC: 21100 AN: 51996

Middle Eastern (MID) AF: 0.305 AC: 1580 AN: 5188

European-Non Finnish (NFE) AF: 0.319 AC: 315594 AN: 990570

Other (OTH) AF: 0.307 AC: 16768 AN: 54624

GnomAD4 genome AF: 0.281 AC: 42711 AN: 152212 Hom.: 6638 Cov.: 34 AF XY: 0.288 AC XY: 21402 AN XY: 74416

African (AFR) AF: 0.138 AC: 5741 AN: 41548

American (AMR) AF: 0.369 AC: 5634 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 976 AN: 3472

East Asian (EAS) AF: 0.374 AC: 1935 AN: 5172

South Asian (SAS) AF: 0.320 AC: 1542 AN: 4822

European-Finnish (FIN) AF: 0.413 AC: 4373 AN: 10586

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21607 AN: 68012

Other (OTH) AF: 0.284 AC: 600 AN: 2116

Alfa AF: 0.301 Hom.: 11760

Bravo AF: 0.270

Asia WGS AF: 0.320 AC: 1112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.73
PhyloP100		-0.13
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: rs3803229; hg19: chr13-111134780; COSMIC: COSV64626249;