13-110449779-C-T

Variant names:

• chr13-110449779-C-T
• rs74941798
• NM_001846.4:c.1179C>T

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.1179C>T​(p.Ile393Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,547,352 control chromosomes in the GnomAD database, including 116,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I393I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8265 hom., cov: 31)
  • Exomes 𝑓: 0.39 (107910 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.96
• Publications: 17 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=-0.7).
• BP6: Variant 13-110449779-C-T is Benign according to our data. Variant chr13-110449779-C-T is described in ClinVar as Benign. ClinVar VariationId is 311120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.402 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.1179C>T	p.Ile393Ile	synonymous	Exon 19 of 48	NP_001837.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.1179C>T	p.Ile393Ile	synonymous	Exon 19 of 48	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.1260C>T	p.Ile420Ile	synonymous	Exon 20 of 49	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.1179C>T	p.Ile393Ile	synonymous	Exon 19 of 48	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46296 AN: 151770 Hom.: 8261 Cov.: 31

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.331 AC: 50178 AN: 151472 AF XY: 0.338

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.387 AC: 540031 AN: 1395464 Hom.: 107910 Cov.: 35 AF XY: 0.386 AC XY: 266009 AN XY: 688346

African (AFR) AF: 0.124 AC: 3902 AN: 31432

American (AMR) AF: 0.195 AC: 6888 AN: 35302

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7390 AN: 25124

East Asian (EAS) AF: 0.261 AC: 9308 AN: 35704

South Asian (SAS) AF: 0.339 AC: 26804 AN: 78956

European-Finnish (FIN) AF: 0.458 AC: 22356 AN: 48836

Middle Eastern (MID) AF: 0.233 AC: 966 AN: 4142

European-Non Finnish (NFE) AF: 0.410 AC: 442171 AN: 1078214

Other (OTH) AF: 0.351 AC: 20246 AN: 57754

GnomAD4 genome AF: 0.305 AC: 46296 AN: 151888 Hom.: 8265 Cov.: 31 AF XY: 0.306 AC XY: 22702 AN XY: 74252

African (AFR) AF: 0.132 AC: 5465 AN: 41454

American (AMR) AF: 0.227 AC: 3467 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1340 AN: 5134

South Asian (SAS) AF: 0.326 AC: 1564 AN: 4802

European-Finnish (FIN) AF: 0.452 AC: 4752 AN: 10520

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27544 AN: 67912

Other (OTH) AF: 0.280 AC: 588 AN: 2102

Alfa AF: 0.343 Hom.: 3650

Bravo AF: 0.278

Asia WGS AF: 0.274 AC: 955 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Porencephaly 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.7
DANN	Benign	0.55
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74941798; hg19: chr13-111102126;