rs62621875

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001846.4(COL4A2):c.3448C>A(p.Gln1150Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,580,738 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 10 hom. )

Consequence

COL4A2
NM_001846.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 4.29

Publications

19 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), G2P, Ambry Genetics
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

new If you want to explore the variant's impact on the transcript NM_001846.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001846.4

BP4

Computational evidence support a benign effect (MetaRNN=0.006136745).

BP6

Variant 13-110491334-C-A is Benign according to our data. Variant chr13-110491334-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 29630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00806 (1228/152274) while in subpopulation AFR AF = 0.0274 (1137/41548). AF 95% confidence interval is 0.026. There are 18 homozygotes in GnomAd4. There are 575 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1228 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.3448C>A	p.Gln1150Lys	missense	Exon 37 of 48	NP_001837.2	P08572

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.3448C>A	p.Gln1150Lys	missense	Exon 37 of 48	ENSP00000353654.5	P08572
COL4A2	ENST00000714399.1		c.3529C>A	p.Gln1177Lys	missense	Exon 38 of 49	ENSP00000519666.1	A0AAQ5BHW7
COL4A2	ENST00000400163.8	TSL:5	c.3448C>A	p.Gln1150Lys	missense	Exon 37 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1225

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.00176

AC:

343

AN:

194902

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.0244

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000571

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.000903

AC:

1290

AN:

1428464

Hom.:

Cov.:

AF XY:

0.000817

AC XY:

578

AN XY:

707570

show subpopulations

African (AFR)

AF:

0.0255

AC:

830

AN:

32546

American (AMR)

AF:

0.00213

AC:

AN:

41320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25600

East Asian (EAS)

AF:

0.00

AC:

AN:

38052

South Asian (SAS)

AF:

0.0000610

AC:

AN:

81926

European-Finnish (FIN)

AF:

0.000156

AC:

AN:

51136

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000205

AC:

224

AN:

1093094

Other (OTH)

AF:

0.00215

AC:

127

AN:

59056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00806

AC:

1228

AN:

152274

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

575

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0274

AC:

1137

AN:

41548

American (AMR)

AF:

0.00373

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68006

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

182

243

304

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:

0.00269

Hom.:

Bravo

AF:

0.00958

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Porencephaly 2 (3)

COL4A2-related disorder (1)

not specified (1)

Porencephaly 2;C3281105:Hemorrhage, intracerebral, susceptibility to (1)

Hemorrhage, intracerebral, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Benign

0.090

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.38

PhyloP100

4.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.33

Sift4G

Benign

0.90

Varity_R

0.25

gMVP

0.67

Mutation Taster

=89/11

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over