Genetic Variant COL4A2:c.2425+250C>A (chr13-110473400-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001846.4(COL4A2):c.2425+250C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 469,094 control chromosomes in the GnomAD database, including 1,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 1156 hom., cov: 33)

Exomes 𝑓: 0.017 ( 296 hom. )

Consequence

COL4A2
NM_001846.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.347

Publications

3 publications found

Variant links:

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

COL4A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 13-110473400-C-A is Benign according to our data. Variant chr13-110473400-C-A is described in ClinVar as Benign. ClinVar VariationId is 1270352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.2425+250C>A		intron_variant	Intron 29 of 47	ENST00000360467.7	NP_001837.2	P08572A0A024RDW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 link	c.2425+250C>A		intron_variant	Intron 29 of 47	5	NM_001846.4	ENSP00000353654.5		P08572

Frequencies

GnomAD3 genomes

AF:

0.0705

AC:

10723

AN:

152142

Hom.:

1150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.0368

Gnomad SAS

AF:

0.0704

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.0535

GnomAD4 exome

AF:

0.0175

AC:

5533

AN:

316834

Hom.:

296

AF XY:

0.0183

AC XY:

2993

AN XY:

163788

show subpopulations

African (AFR)

AF:

0.230

AC:

1721

AN:

7486

American (AMR)

AF:

0.0200

AC:

205

AN:

10234

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

179

AN:

10770

East Asian (EAS)

AF:

0.0551

AC:

1218

AN:

22088

South Asian (SAS)

AF:

0.0616

AC:

1379

AN:

22400

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

23764

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

1542

European-Non Finnish (NFE)

AF:

0.00143

AC:

285

AN:

198688

Other (OTH)

AF:

0.0261

AC:

519

AN:

19862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0707

AC:

10758

AN:

152260

Hom.:

1156

Cov.:

AF XY:

0.0681

AC XY:

5072

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.229

AC:

9487

AN:

41508

American (AMR)

AF:

0.0297

AC:

455

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.0367

AC:

190

AN:

5178

South Asian (SAS)

AF:

0.0704

AC:

340

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

68032

Other (OTH)

AF:

0.0529

AC:

112

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

424

848

1273

1697

2121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0540

Hom.:

Bravo

AF:

0.0789

Asia WGS

AF:

0.0750

AC:

263

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.84

CADD

Benign

1.7

(source)

DANN

Benign

0.51

PhyloP100

-0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over