13-110467049-G-A

Variant names:

• chr13-110467049-G-A
• rs3803230
• NM_001846.4:c.2048G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001846.4(COL4A2):​c.2048G>A​(p.Gly683Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G683V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19112355).

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.2048G>A	p.Gly683Glu	missense	Exon 27 of 48	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.2048G>A	p.Gly683Glu	missense	Exon 27 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.2129G>A	p.Gly710Glu	missense	Exon 28 of 49	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.2048G>A	p.Gly683Glu	missense	Exon 27 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.2
DANN	Benign	0.81
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	0.78	N
PhyloP100		0.65
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.22
Sift	Benign	0.56	T
Sift4G	Benign	0.19	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0676)
MVP		0.79
MPC		0.99
ClinPred		0.10	T
GERP RS		1.4
PromoterAI		0.014	Neutral
Varity_R		0.026
gMVP		0.49
Mutation Taster		=93/7	polymorphism

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: rs3803230; hg19: chr13-111119396;