chr13-110449695-G-A

Variant names:

• chr13-110449695-G-A
• rs76425569
• NM_001846.4:c.1095G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.1095G>A​(p.Pro365Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,547,466 control chromosomes in the GnomAD database, including 100,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7158 hom., cov: 32)
  • Exomes 𝑓: 0.36 (93534 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.375
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-110449695-G-A is Benign according to our data. Variant chr13-110449695-G-A is described in ClinVar as Benign. ClinVar VariationId is 311119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.375 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1095G>A	p.Pro365Pro	synonymous_variant	Exon 19 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1095G>A	p.Pro365Pro	synonymous_variant	Exon 19 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43333 AN: 151838 Hom.: 7153 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.309 AC: 47279 AN: 152798 AF XY: 0.317

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.361 AC: 503171 AN: 1395510 Hom.: 93534 Cov.: 35 AF XY: 0.361 AC XY: 248155 AN XY: 687962

African (AFR) AF: 0.123 AC: 3852 AN: 31432

American (AMR) AF: 0.179 AC: 6289 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6890 AN: 25122

East Asian (EAS) AF: 0.270 AC: 9628 AN: 35642

South Asian (SAS) AF: 0.329 AC: 26022 AN: 79092

European-Finnish (FIN) AF: 0.407 AC: 19995 AN: 49174

Middle Eastern (MID) AF: 0.205 AC: 1074 AN: 5242

European-Non Finnish (NFE) AF: 0.381 AC: 410503 AN: 1076796

Other (OTH) AF: 0.327 AC: 18918 AN: 57810

GnomAD4 genome AF: 0.285 AC: 43341 AN: 151956 Hom.: 7158 Cov.: 32 AF XY: 0.286 AC XY: 21206 AN XY: 74264

African (AFR) AF: 0.128 AC: 5314 AN: 41458

American (AMR) AF: 0.207 AC: 3167 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1379 AN: 5148

South Asian (SAS) AF: 0.319 AC: 1537 AN: 4814

European-Finnish (FIN) AF: 0.405 AC: 4268 AN: 10542

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25664 AN: 67930

Other (OTH) AF: 0.260 AC: 548 AN: 2106

Alfa AF: 0.335 Hom.: 4650

Bravo AF: 0.260

Asia WGS AF: 0.278 AC: 970 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Porencephaly 2 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.6
DANN	Benign	0.79
PhyloP100		-0.38
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: rs76425569; hg19: chr13-111102042; COSMIC: COSV64626275;