rs749501904

Positions:

chr13-110424843-G-A

Variant summary

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

The NM_001846.4(COL4A2):c.290G>A(p.Gly97Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,022 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.43

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, 0.978

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4 linkuse as main transcript	c.290G>A	p.Gly97Glu	missense_variant	5/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL4A2	ENST00000360467.7 linkuse as main transcript	c.290G>A	p.Gly97Glu	missense_variant	5/48	5	NM_001846.4	ENSP00000353654	P1
COL4A2	ENST00000650540.1 linkuse as main transcript	c.290G>A	p.Gly97Glu	missense_variant	5/18			ENSP00000497878
COL4A2	ENST00000400163.7 linkuse as main transcript	c.290G>A	p.Gly97Glu	missense_variant	5/5	5		ENSP00000383027
COL4A2	ENST00000619688.2 linkuse as main transcript	c.44G>A	p.Gly15Glu	missense_variant	1/3			ENSP00000496868

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000641

AC:

AN:

249512

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	COL4A2: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 97 of the COL4A2 protein (p.Gly97Glu). This variant is present in population databases (rs749501904, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COL4A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 521905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.87

D;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.5

.;H;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.4

D;D;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.94

MVP

0.99

MPC

1.2

ClinPred

0.99

GERP RS

5.1

Varity_R

0.84

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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