chr13-110512039-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_001846.4(COL4A2):c.4987G>A(p.Gly1663Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,613,506 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1663R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 3 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 9.54

Publications

7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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:

ENSG00000289010 (HGNC:):

ENSG00000289010 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.815

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000401 (61/152292) while in subpopulation NFE AF = 0.000838 (57/68022). AF 95% confidence interval is 0.000664. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 61 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.4987G>A	p.Gly1663Ser	missense	Exon 48 of 48	NP_001837.2	P08572

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.4987G>A	p.Gly1663Ser	missense	Exon 48 of 48	ENSP00000353654.5	P08572
COL4A2	ENST00000714399.1		c.5068G>A	p.Gly1690Ser	missense	Exon 49 of 49	ENSP00000519666.1	A0AAQ5BHW7
COL4A2	ENST00000400163.8	TSL:5	c.4987G>A	p.Gly1663Ser	missense	Exon 48 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000498

AC:

124

AN:

248916

AF XY:

0.000518

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000753

AC:

1100

AN:

1461214

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

531

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000379

AC:

AN:

52748

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000938

AC:

1043

AN:

1112010

Other (OTH)

AF:

0.000613

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000401

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000914

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00118

AC:

ExAC

AF:

0.000595

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Porencephaly 2 (2)

Inborn genetic diseases (1)

Optic nerve hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

PhyloP100

9.5

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MVP

0.95

MPC

0.30

ClinPred

0.14

GERP RS

4.9

Varity_R

0.91

gMVP

0.80

Mutation Taster

=22/78

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over