NM_001846.4:c.3634+47G>C

Variant names:

• chr13-110493329-G-C
• rs2391833
• NM_001846.4:c.3634+47G>C

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.3634+47G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,597,572 control chromosomes in the GnomAD database, including 238,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16864 hom., cov: 32)
  • Exomes 𝑓: 0.55 (222113 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.465
• 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: 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 13-110493329-G-C is Benign according to our data. Variant chr13-110493329-G-C is described in ClinVar as Benign. ClinVar VariationId is 1289388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

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.3634+47G>C		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.3634+47G>C		intron	N/A	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.3715+47G>C		intron	N/A	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.3634+47G>C		intron	N/A	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66934 AN: 151958 Hom.: 16860 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.516 AC: 126383 AN: 245128 AF XY: 0.520

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.576

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.532

GnomAD4 exome AF: 0.549 AC: 793864 AN: 1445494 Hom.: 222113 Cov.: 27 AF XY: 0.549 AC XY: 395220 AN XY: 719906

African (AFR) AF: 0.158 AC: 5216 AN: 33102

American (AMR) AF: 0.512 AC: 22668 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12488 AN: 26002

East Asian (EAS) AF: 0.555 AC: 21953 AN: 39570

South Asian (SAS) AF: 0.493 AC: 42307 AN: 85842

European-Finnish (FIN) AF: 0.492 AC: 26059 AN: 52922

Middle Eastern (MID) AF: 0.551 AC: 3158 AN: 5736

European-Non Finnish (NFE) AF: 0.573 AC: 628809 AN: 1098148

Other (OTH) AF: 0.521 AC: 31206 AN: 59872

GnomAD4 genome AF: 0.440 AC: 66950 AN: 152078 Hom.: 16864 Cov.: 32 AF XY: 0.441 AC XY: 32744 AN XY: 74326

African (AFR) AF: 0.174 AC: 7220 AN: 41506

American (AMR) AF: 0.488 AC: 7457 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3466

East Asian (EAS) AF: 0.561 AC: 2892 AN: 5158

South Asian (SAS) AF: 0.482 AC: 2323 AN: 4816

European-Finnish (FIN) AF: 0.488 AC: 5155 AN: 10570

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38523 AN: 67954

Other (OTH) AF: 0.462 AC: 975 AN: 2110

Alfa AF: 0.424 Hom.: 2258

Bravo AF: 0.431

Asia WGS AF: 0.540 AC: 1879 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	2.6
DANN	Benign	0.75
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2391833; hg19: chr13-111145676; COSMIC: COSV104422508;