13-110446698-C-G

Variant names:

• chr13-110446698-C-G
• rs59905747
• NM_001846.4:c.1012-100C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.1012-100C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.085 in 978,070 control chromosomes in the GnomAD database, including 4,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (748 hom., cov: 33)
  • Exomes 𝑓: 0.084 (4123 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.186
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 13-110446698-C-G is Benign according to our data. Variant chr13-110446698-C-G is described in ClinVar as Benign. ClinVar VariationId is 1231605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.1012-100C>G		intron	N/A	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.1012-100C>G		intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.1093-100C>G		intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.1012-100C>G		intron	N/A	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.0896 AC: 13625 AN: 152104 Hom.: 739 Cov.: 33

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0841 AC: 69451 AN: 825848 Hom.: 4123 AF XY: 0.0818 AC XY: 34751 AN XY: 424912

African (AFR) AF: 0.0820 AC: 1702 AN: 20748

American (AMR) AF: 0.177 AC: 7016 AN: 39638

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 2578 AN: 18512

East Asian (EAS) AF: 0.274 AC: 8934 AN: 32634

South Asian (SAS) AF: 0.0466 AC: 2974 AN: 63832

European-Finnish (FIN) AF: 0.0796 AC: 2670 AN: 33556

Middle Eastern (MID) AF: 0.0746 AC: 282 AN: 3778

European-Non Finnish (NFE) AF: 0.0695 AC: 40075 AN: 576972

Other (OTH) AF: 0.0890 AC: 3220 AN: 36178

GnomAD4 genome AF: 0.0897 AC: 13661 AN: 152222 Hom.: 748 Cov.: 33 AF XY: 0.0902 AC XY: 6712 AN XY: 74430

African (AFR) AF: 0.0805 AC: 3343 AN: 41536

American (AMR) AF: 0.141 AC: 2162 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3470

East Asian (EAS) AF: 0.252 AC: 1301 AN: 5154

South Asian (SAS) AF: 0.0533 AC: 257 AN: 4820

European-Finnish (FIN) AF: 0.0874 AC: 928 AN: 10612

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4840 AN: 68018

Other (OTH) AF: 0.102 AC: 214 AN: 2108

Alfa AF: 0.0775 Hom.: 65

Bravo AF: 0.0975

Asia WGS AF: 0.132 AC: 459 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.3
DANN	Benign	0.30
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59905747; hg19: chr13-111099045; COSMIC: COSV64636511;