rs75082326

Variant names:

• chr13-110449605-A-G
• rs75082326
• NM_001846.4:c.1079-74A>G

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.1079-74A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,391,932 control chromosomes in the GnomAD database, including 85,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6996 hom., cov: 32)
  • Exomes 𝑓: 0.35 (78779 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.24
• 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=-0.92).
• BP6: Variant 13-110449605-A-G is Benign according to our data. Variant chr13-110449605-A-G is described in ClinVar as Benign. ClinVar VariationId is 1241514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1079-74A>G		intron_variant	Intron 18 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1079-74A>G		intron_variant	Intron 18 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42334 AN: 151988 Hom.: 6992 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.351 AC: 434702 AN: 1239826 Hom.: 78779 AF XY: 0.351 AC XY: 213992 AN XY: 608806

African (AFR) AF: 0.0966 AC: 2645 AN: 27374

American (AMR) AF: 0.188 AC: 4126 AN: 21936

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 5253 AN: 20590

East Asian (EAS) AF: 0.268 AC: 9205 AN: 34308

South Asian (SAS) AF: 0.335 AC: 22584 AN: 67404

European-Finnish (FIN) AF: 0.406 AC: 18988 AN: 46758

Middle Eastern (MID) AF: 0.202 AC: 1037 AN: 5130

European-Non Finnish (NFE) AF: 0.367 AC: 354464 AN: 964606

Other (OTH) AF: 0.317 AC: 16400 AN: 51720

GnomAD4 genome AF: 0.278 AC: 42335 AN: 152106 Hom.: 6996 Cov.: 32 AF XY: 0.279 AC XY: 20766 AN XY: 74338

African (AFR) AF: 0.108 AC: 4499 AN: 41536

American (AMR) AF: 0.207 AC: 3158 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 949 AN: 3468

East Asian (EAS) AF: 0.269 AC: 1386 AN: 5154

South Asian (SAS) AF: 0.324 AC: 1562 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4274 AN: 10568

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25520 AN: 67956

Other (OTH) AF: 0.255 AC: 539 AN: 2110

Alfa AF: 0.308 Hom.: 1470

Bravo AF: 0.252

Asia WGS AF: 0.273 AC: 953 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

- -

Jun 29, 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	-0.92
CADD	Benign	0.0010
DANN	Benign	0.20
PhyloP100		-6.2
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: rs75082326; hg19: chr13-111101952; COSMIC: COSV64636531;