NM_001846.4:c.2203+176T>C

Variant names:

• chr13-110469500-T-C
• rs9515230
• NM_001846.4:c.2203+176T>C

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.2203+176T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 152,276 control chromosomes in the GnomAD database, including 636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.083 (636 hom., cov: 33)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72
• 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=-0.91).
• BP6: Variant 13-110469500-T-C is Benign according to our data. Variant chr13-110469500-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2203+176T>C		intron_variant	Intron 28 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2203+176T>C		intron_variant	Intron 28 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0835 AC: 12710 AN: 152158 Hom.: 638 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0834 AC: 12705 AN: 152276 Hom.: 636 Cov.: 33 AF XY: 0.0832 AC XY: 6194 AN XY: 74454

African (AFR) AF: 0.0330 AC: 1372 AN: 41556

American (AMR) AF: 0.102 AC: 1567 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.109 AC: 564 AN: 5188

South Asian (SAS) AF: 0.104 AC: 503 AN: 4820

European-Finnish (FIN) AF: 0.0738 AC: 783 AN: 10612

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7067 AN: 68020

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.104 Hom.: 1122

Bravo AF: 0.0862

Asia WGS AF: 0.0990 AC: 344 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.45
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9515230; hg19: chr13-111121847; COSMIC: COSV64628677;