rs62621885

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001846.4(COL4A2):c.574G>T(p.Val192Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00859 in 1,614,134 control chromosomes in the GnomAD database, including 117 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V192V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0073 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 110 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.363

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011219263).

BP6

Variant 13-110430425-G-T is Benign according to our data. Variant chr13-110430425-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 311106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00728 (1108/152298) while in subpopulation AMR AF = 0.0247 (378/15298). AF 95% confidence interval is 0.0227. There are 7 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.574G>T	p.Val192Phe	missense_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.574G>T	p.Val192Phe	missense_variant	Exon 9 of 48	5	NM_001846.4	ENSP00000353654.5		P08572

Frequencies

GnomAD3 genomes

AF:

0.00726

AC:

1105

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00791

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.0103

AC:

2580

AN:

249466

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.0332

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.000649

Gnomad NFE exome

AF:

0.00728

Gnomad OTH exome

AF:

0.00842

GnomAD4 exome

AF:

0.00873

AC:

12758

AN:

1461836

Hom.:

110

Cov.:

AF XY:

0.00901

AC XY:

6554

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33468

American (AMR)

AF:

0.0325

AC:

1453

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26134

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0166

AC:

1429

AN:

86244

European-Finnish (FIN)

AF:

0.000936

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00833

AC:

9264

AN:

1112002

Other (OTH)

AF:

0.00727

AC:

439

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

748

1496

2245

2993

3741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.00728

AC:

1108

AN:

152298

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

560

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

41562

American (AMR)

AF:

0.0247

AC:

378

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0154

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00791

AC:

538

AN:

68030

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00692

Hom.:

Bravo

AF:

0.00869

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00111

AC:

ESP6500EA

AF:

0.00774

AC:

ExAC

AF:

0.00950

AC:

1147

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 03, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Porencephaly 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.4

L;.

PhyloP100

0.36

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.40

T;.

Sift4G

Benign

0.064

T;.

Polyphen

0.85

P;.

Vest4

0.24

MPC

0.72

ClinPred

0.0058

GERP RS

3.1

Varity_R

0.081

gMVP

0.53

Mutation Taster

=87/13

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

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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