chr13-110430402-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001846.4(COL4A2):c.551G>A(p.Gly184Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G184S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

COL4A2
NM_001846.4 missense, splice_region

Scores

Splicing: ADA: 0.4932

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.551G>A	p.Gly184Asp	missense_variant, splice_region_variant	Exon 9 of 48	ENST00000360467.7	NP_001837.2	P08572A0A024RDW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 link	c.551G>A	p.Gly184Asp	missense_variant, splice_region_variant	Exon 9 of 48	5	NM_001846.4	ENSP00000353654.5		P08572

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726996

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111934

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.055673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Joint hypermobility

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.9

H;.

PhyloP100

6.1

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.9

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.0050

D;.

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.65

Loss of methylation at R183 (P = 0.0497);Loss of methylation at R183 (P = 0.0497);

MVP

0.97

MPC

1.2

ClinPred

0.99

GERP RS

5.2

Varity_R

0.60

gMVP

0.96

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.49

dbscSNV1_RF

Benign

0.33

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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chr13-110430402-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over