NM_001846.4:c.2185G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2

The NM_001846.4(COL4A2):c.2185G>A(p.Gly729Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000218 in 1,589,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G729G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.70

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: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

BP6

Variant 13-110469306-G-A is Benign according to our data. Variant chr13-110469306-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496734.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.2185G>A	p.Gly729Arg	missense_variant	Exon 28 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 link	c.2185G>A	p.Gly729Arg	missense_variant	Exon 28 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000169

AC:

AN:

200946

AF XY:

0.000166

show subpopulations

Gnomad AFR exome

AF:

0.0000873

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000573

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

322

AN:

1437208

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

161

AN XY:

712332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.0000242

AC:

AN:

41362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25582

East Asian (EAS)

AF:

0.00

AC:

AN:

38940

South Asian (SAS)

AF:

0.00

AC:

AN:

82168

European-Finnish (FIN)

AF:

0.0000774

AC:

AN:

51678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5042

European-Non Finnish (NFE)

AF:

0.000278

AC:

306

AN:

1099964

Other (OTH)

AF:

0.000185

AC:

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41422

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000311

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000242

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL4A2 c.2185G>A (p.Gly729Arg) results in a non-conservative amino acid change to a highly conserved residue located in a Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 200946 control chromosomes, allowing no conclusion about variant significance. c.2185G>A has been reported in the literature in an individual affected with optic nerve hypoplasia and hypertelorism, as well as their unaffected mother (Dahl_2020). This report does not provide unequivocal conclusions about association of the variant with Porencephaly 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

COL4A2-related disorder

Uncertain:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The COL4A2 c.2185G>A variant is predicted to result in the amino acid substitution p.Gly729Arg. This variant was reported in an individual with optic nerve hypoplasia, but it was inherited from a healthy parent (Dahl et al 2020. PubMed ID: 32040484). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant results in a glycine substitution in the collagen triple helical region of the COL4A2 protein, and substitutions of this type are frequently pathogenic (Fidler et al. 2018. PubMed ID: 29632050). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

See cases

Uncertain:1

Dec 08, 2021

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM2,PP3,BP1 -

Optic nerve hypoplasia

Uncertain:1

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Jan 10, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.4

PhyloP100

4.7

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.93

Sift

Benign

0.043

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.86

MutPred

1.0

Gain of methylation at G729 (P = 0.0238);

MVP

0.95

MPC

1.0

ClinPred

0.92

GERP RS

5.6

Varity_R

0.83

gMVP

0.98

Mutation Taster

=52/48

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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