Genetic Variant NM_001846.4:c.99+20537C>G (chr13-110328660-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001846.4(COL4A2):c.99+20537C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,028 control chromosomes in the GnomAD database, including 10,785 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 10783 hom., cov: 32)

Exomes 𝑓: 0.45 ( 2 hom. )

Consequence

COL4A2
NM_001846.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0930

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.99+20537C>G		intron_variant	Intron 3 of 47	ENST00000360467.7	NP_001837.2	P08572A0A024RDW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 link	c.99+20537C>G		intron_variant	Intron 3 of 47	5	NM_001846.4	ENSP00000353654.5		P08572

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54406

AN:

151888

Hom.:

10778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.442

Gnomad OTH

AF:

0.320

GnomAD4 exome

AF:

0.455

AC:

AN:

Hom.:

AF XY:

0.400

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.450

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.358

AC:

54447

AN:

152006

Hom.:

10783

Cov.:

AF XY:

0.361

AC XY:

26854

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.207

AC:

8576

AN:

41478

American (AMR)

AF:

0.334

AC:

5094

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1118

AN:

3472

East Asian (EAS)

AF:

0.253

AC:

1309

AN:

5176

South Asian (SAS)

AF:

0.361

AC:

1735

AN:

4812

European-Finnish (FIN)

AF:

0.515

AC:

5426

AN:

10540

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.442

AC:

30049

AN:

67950

Other (OTH)

AF:

0.319

AC:

674

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1733

3466

5200

6933

8666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.277

Hom.:

808

Bravo

AF:

0.334

Asia WGS

AF:

0.325

AC:

1130

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.6

(source)

DANN

Benign

0.38

PhyloP100

-0.093

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over