rs200735885

Positions:

chr13-110465576-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001846.4(COL4A2):c.1948C>T(p.Pro650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,708 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.433

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021291971).

BP6

Variant 13-110465576-C-T is Benign according to our data. Variant chr13-110465576-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311138.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr13-110465576-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00165 (252/152334) while in subpopulation AMR AF= 0.00203 (31/15308). AF 95% confidence interval is 0.00162. There are 2 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A2	NM_001846.4 linkuse as main transcript	c.1948C>T	p.Pro650Ser	missense_variant	25/48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 linkuse as main transcript	c.1948C>T	p.Pro650Ser	missense_variant	25/48	5	NM_001846.4	ENSP00000353654	P1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00186

AC:

459

AN:

246218

Hom.:

AF XY:

0.00185

AC XY:

248

AN XY:

134004

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.000799

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00534

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00174

AC:

2549

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000928

Gnomad4 FIN exome

AF:

0.00573

Gnomad4 NFE exome

AF:

0.00177

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00165

AC:

252

AN:

152334

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00183

AC:

ExAC

AF:

0.00172

AC:

208

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	This variant is associated with the following publications: (PMID: 24036952) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	COL4A2: BS1, BS2 -

Optic nerve hypoplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Feb 14, 2018

COL4A2 mutations have been seen in optic nerve hypoplasia previously and the penetrance has been shown to be highly varying even within families. -

COL4A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Porencephaly 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.042

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.21

Sift

Benign

0.11

Sift4G

Benign

0.088

Polyphen

0.011

Vest4

0.31

MVP

0.82

MPC

0.49

ClinPred

0.013

GERP RS

2.1

Varity_R

0.057

gMVP

0.37

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