rs56269522

Variant names:

• chr13-110432309-C-T
• rs56269522
• NM_001846.4:c.649-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001846.4(COL4A2):​c.649-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,600,714 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.735
• Publications: 1 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=-0.8).
• BP6: Variant 13-110432309-C-T is Benign according to our data. Variant chr13-110432309-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1756/152182) while in subpopulation AFR AF = 0.0403 (1673/41514). AF 95% confidence interval is 0.0387. There are 27 homozygotes in GnomAd4. There are 809 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1756 AD gene.

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.649-16C>T		intron	N/A	NP_001837.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.649-16C>T		intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.649-16C>T		intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.649-16C>T		intron	N/A	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1746 AN: 152062 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00302 AC: 719 AN: 238114 AF XY: 0.00233

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.00113 AC: 1640 AN: 1448532 Hom.: 29 Cov.: 30 AF XY: 0.000984 AC XY: 709 AN XY: 720628

African (AFR) AF: 0.0404 AC: 1317 AN: 32592

American (AMR) AF: 0.00226 AC: 94 AN: 41558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.000108 AC: 9 AN: 83354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53146

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5704

European-Non Finnish (NFE) AF: 0.0000262 AC: 29 AN: 1107510

Other (OTH) AF: 0.00305 AC: 182 AN: 59726

GnomAD4 genome AF: 0.0115 AC: 1756 AN: 152182 Hom.: 27 Cov.: 32 AF XY: 0.0109 AC XY: 809 AN XY: 74392

African (AFR) AF: 0.0403 AC: 1673 AN: 41514

American (AMR) AF: 0.00419 AC: 64 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0110 Hom.: 23

Bravo AF: 0.0132

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.36
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

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: rs56269522; hg19: chr13-111084656;