rs76536922

Variant names:

• chr13-110307817-C-T
• rs76536922
• NM_001846.4:c.-44-43C>T

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.-44-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,489,710 control chromosomes in the GnomAD database, including 3,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (244 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2816 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.359
• 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=-0.86).
• BP6: Variant 13-110307817-C-T is Benign according to our data. Variant chr13-110307817-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.-44-43C>T		intron_variant	Intron 1 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.-44-43C>T		intron_variant	Intron 1 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7816 AN: 152148 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.0631

GnomAD4 exome AF: 0.0623 AC: 83361 AN: 1337444 Hom.: 2816 Cov.: 27 AF XY: 0.0624 AC XY: 40808 AN XY: 653870

African (AFR) AF: 0.0226 AC: 688 AN: 30398

American (AMR) AF: 0.0337 AC: 1163 AN: 34488

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 1554 AN: 20688

East Asian (EAS) AF: 0.0303 AC: 1134 AN: 37386

South Asian (SAS) AF: 0.0557 AC: 3968 AN: 71270

European-Finnish (FIN) AF: 0.0548 AC: 2588 AN: 47198

Middle Eastern (MID) AF: 0.0901 AC: 351 AN: 3896

European-Non Finnish (NFE) AF: 0.0662 AC: 68718 AN: 1037326

Other (OTH) AF: 0.0583 AC: 3197 AN: 54794

GnomAD4 genome AF: 0.0513 AC: 7817 AN: 152266 Hom.: 244 Cov.: 32 AF XY: 0.0514 AC XY: 3826 AN XY: 74452

African (AFR) AF: 0.0245 AC: 1020 AN: 41566

American (AMR) AF: 0.0491 AC: 751 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.0272 AC: 140 AN: 5154

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4828

European-Finnish (FIN) AF: 0.0593 AC: 629 AN: 10606

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0659 AC: 4484 AN: 68014

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

Alfa AF: 0.0538 Hom.: 36

Bravo AF: 0.0485

Asia WGS AF: 0.0420 AC: 147 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.87
PhyloP100		0.36
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76536922; hg19: chr13-110960164;