rs201058867

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4 linkuse as main transcript	c.2185G>A	p.Gly729Arg	missense_variant	28/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7 linkuse as main transcript	c.2185G>A	p.Gly729Arg	missense_variant	28/48	5	NM_001846.4	P1
COL4A2	ENST00000494852.2 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant	2/4	3

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

GnomAD3 exomes

AF:

0.000169

AC:

AN:

200946

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

108178

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000774

Gnomad4 NFE exome

AF:

0.000278

Gnomad4 OTH exome

AF:

0.000185

GnomAD4 genome

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000228

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 28, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PM2,PP3,BP1 -

Optic nerve hypoplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over