rs403839

Variant names:

• chr13-110491974-G-A
• rs403839
• NM_001846.4:c.3455-96G>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.3455-96G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,070,718 control chromosomes in the GnomAD database, including 6,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1018 hom., cov: 33)
  • Exomes 𝑓: 0.11 (5775 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0150
• Publications: 5 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=-0.86).
• BP6: Variant 13-110491974-G-A is Benign according to our data. Variant chr13-110491974-G-A is described in ClinVar as Benign. ClinVar VariationId is 1289440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.3455-96G>A		intron_variant	Intron 37 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.3455-96G>A		intron_variant	Intron 37 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17339 AN: 152088 Hom.: 1015 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0662

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0696

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0969

GnomAD4 exome AF: 0.108 AC: 99269 AN: 918512 Hom.: 5775 AF XY: 0.107 AC XY: 48903 AN XY: 458916

African (AFR) AF: 0.130 AC: 2657 AN: 20494

American (AMR) AF: 0.112 AC: 2168 AN: 19318

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1043 AN: 17158

East Asian (EAS) AF: 0.127 AC: 4078 AN: 32114

South Asian (SAS) AF: 0.0668 AC: 3572 AN: 53462

European-Finnish (FIN) AF: 0.0840 AC: 3236 AN: 38510

Middle Eastern (MID) AF: 0.0608 AC: 262 AN: 4308

European-Non Finnish (NFE) AF: 0.113 AC: 77883 AN: 691586

Other (OTH) AF: 0.105 AC: 4370 AN: 41562

GnomAD4 genome AF: 0.114 AC: 17359 AN: 152206 Hom.: 1018 Cov.: 33 AF XY: 0.113 AC XY: 8375 AN XY: 74418

African (AFR) AF: 0.134 AC: 5564 AN: 41524

American (AMR) AF: 0.100 AC: 1537 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 230 AN: 3472

East Asian (EAS) AF: 0.167 AC: 863 AN: 5166

South Asian (SAS) AF: 0.0697 AC: 336 AN: 4824

European-Finnish (FIN) AF: 0.0743 AC: 788 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7650 AN: 68000

Other (OTH) AF: 0.0974 AC: 206 AN: 2116

Alfa AF: 0.114 Hom.: 159

Bravo AF: 0.119

Asia WGS AF: 0.106 AC: 366 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

- -

Jul 09, 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	-0.86
CADD	Benign	4.0
DANN	Benign	0.63
PhyloP100		-0.015
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: rs403839; hg19: chr13-111144321; COSMIC: COSV64627356;