rs2296851

Variant names:

• chr13-110485908-G-A
• rs2296851
• NM_001846.4:c.3207+72G>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.3207+72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,581,824 control chromosomes in the GnomAD database, including 14,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1400 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13149 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290
• Publications: 7 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=-0.87).
• BP6: Variant 13-110485908-G-A is Benign according to our data. Variant chr13-110485908-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.3207+72G>A		intron_variant	Intron 34 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.3207+72G>A		intron_variant	Intron 34 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20623 AN: 152066 Hom.: 1397 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.134 AC: 191168 AN: 1429640 Hom.: 13149 AF XY: 0.133 AC XY: 94103 AN XY: 709254

African (AFR) AF: 0.161 AC: 5150 AN: 32008

American (AMR) AF: 0.125 AC: 4719 AN: 37664

Ashkenazi Jewish (ASJ) AF: 0.0996 AC: 2507 AN: 25164

East Asian (EAS) AF: 0.113 AC: 4417 AN: 38974

South Asian (SAS) AF: 0.120 AC: 9995 AN: 82972

European-Finnish (FIN) AF: 0.116 AC: 5937 AN: 51118

Middle Eastern (MID) AF: 0.0931 AC: 454 AN: 4874

European-Non Finnish (NFE) AF: 0.137 AC: 150359 AN: 1097936

Other (OTH) AF: 0.129 AC: 7630 AN: 58930

GnomAD4 genome AF: 0.136 AC: 20645 AN: 152184 Hom.: 1400 Cov.: 32 AF XY: 0.135 AC XY: 10068 AN XY: 74404

African (AFR) AF: 0.160 AC: 6632 AN: 41518

American (AMR) AF: 0.109 AC: 1671 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 380 AN: 3468

East Asian (EAS) AF: 0.156 AC: 804 AN: 5168

South Asian (SAS) AF: 0.121 AC: 581 AN: 4818

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8983 AN: 67992

Other (OTH) AF: 0.125 AC: 264 AN: 2114

Alfa AF: 0.134 Hom.: 5331

Bravo AF: 0.138

Asia WGS AF: 0.117 AC: 408 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	-0.87
CADD	Benign	2.0
DANN	Benign	0.61
PhyloP100		-0.029
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: rs2296851; hg19: chr13-111138255; COSMIC: COSV64636527; COSMIC: COSV64636527;