13-110491194-G-A

Variant names:

• chr13-110491194-G-A
• rs35120918
• NM_001846.4:c.3347-39G>A

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.3347-39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,437,422 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (76 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.11
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=-0.9).
• BP6: Variant 13-110491194-G-A is Benign according to our data. Variant chr13-110491194-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1198088.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 = 0.0104 (1581/152292) while in subpopulation AFR AF = 0.0143 (593/41566). AF 95% confidence interval is 0.0133. There are 10 homozygotes in GnomAd4. There are 698 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1581 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.3347-39G>A		intron	N/A	NP_001837.2	P08572

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.3347-39G>A		intron	N/A	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.3428-39G>A		intron	N/A	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.3347-39G>A		intron	N/A	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1579 AN: 152174 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00764 AC: 1267 AN: 165876 AF XY: 0.00758

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.00392

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00345

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00895

GnomAD4 exome AF: 0.0104 AC: 13349 AN: 1285130 Hom.: 76 Cov.: 19 AF XY: 0.0101 AC XY: 6473 AN XY: 640746

African (AFR) AF: 0.0152 AC: 447 AN: 29360

American (AMR) AF: 0.00871 AC: 323 AN: 37090

Ashkenazi Jewish (ASJ) AF: 0.00530 AC: 130 AN: 24544

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35750

South Asian (SAS) AF: 0.00114 AC: 88 AN: 77438

European-Finnish (FIN) AF: 0.00383 AC: 190 AN: 49668

Middle Eastern (MID) AF: 0.00256 AC: 13 AN: 5076

European-Non Finnish (NFE) AF: 0.0120 AC: 11625 AN: 972060

Other (OTH) AF: 0.00983 AC: 532 AN: 54144

GnomAD4 genome AF: 0.0104 AC: 1581 AN: 152292 Hom.: 10 Cov.: 33 AF XY: 0.00937 AC XY: 698 AN XY: 74474

African (AFR) AF: 0.0143 AC: 593 AN: 41566

American (AMR) AF: 0.0102 AC: 156 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 719 AN: 68020

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00809 Hom.: 4

Bravo AF: 0.0111

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.45
PhyloP100		-2.1
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: rs35120918; hg19: chr13-111143541;