NM_001846.4:c.2096-120C>A

Variant names:

• chr13-110469097-C-A
• rs9559813
• NM_001846.4:c.2096-120C>A

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.2096-120C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,123,912 control chromosomes in the GnomAD database, including 123,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19563 hom., cov: 33)
  • Exomes 𝑓: 0.46 (104332 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.48
• Publications: 4 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=-0.85).
• BP6: Variant 13-110469097-C-A is Benign according to our data. Variant chr13-110469097-C-A is described in ClinVar as Benign. ClinVar VariationId is 1221711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2096-120C>A		intron_variant	Intron 27 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2096-120C>A		intron_variant	Intron 27 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74954 AN: 151898 Hom.: 19534 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.479

GnomAD4 exome AF: 0.458 AC: 444899 AN: 971896 Hom.: 104332 AF XY: 0.455 AC XY: 220448 AN XY: 484670

African (AFR) AF: 0.656 AC: 14680 AN: 22382

American (AMR) AF: 0.304 AC: 8170 AN: 26854

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 8412 AN: 18394

East Asian (EAS) AF: 0.172 AC: 5664 AN: 32906

South Asian (SAS) AF: 0.362 AC: 21492 AN: 59386

European-Finnish (FIN) AF: 0.375 AC: 16824 AN: 44816

Middle Eastern (MID) AF: 0.518 AC: 2382 AN: 4600

European-Non Finnish (NFE) AF: 0.483 AC: 347739 AN: 719606

Other (OTH) AF: 0.455 AC: 19536 AN: 42952

GnomAD4 genome AF: 0.494 AC: 75043 AN: 152016 Hom.: 19563 Cov.: 33 AF XY: 0.482 AC XY: 35830 AN XY: 74298

African (AFR) AF: 0.649 AC: 26881 AN: 41436

American (AMR) AF: 0.388 AC: 5925 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3472

East Asian (EAS) AF: 0.180 AC: 934 AN: 5186

South Asian (SAS) AF: 0.352 AC: 1699 AN: 4826

European-Finnish (FIN) AF: 0.356 AC: 3763 AN: 10558

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32458 AN: 67944

Other (OTH) AF: 0.480 AC: 1015 AN: 2116

Alfa AF: 0.460 Hom.: 10464

Bravo AF: 0.499

Asia WGS AF: 0.298 AC: 1037 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.78
DANN	Benign	0.54
PhyloP100		-1.5
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: rs9559813; hg19: chr13-111121444;