rs3803230

chr13-110467049-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):c.2048G>C(p.Gly683Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,708 control chromosomes in the GnomAD database, including 8,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (838 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8024 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.651

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043233335).
• BP6: Variant 13-110467049-G-C is Benign according to our data. Variant chr13-110467049-G-C is described in ClinVar as [Benign]. Clinvar id is 311143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110467049-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.2048G>C	p.Gly683Ala	missense_variant	27/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.2048G>C	p.Gly683Ala	missense_variant	27/48	5	NM_001846.4	P1
COL4A2	ENST00000494852.2			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15518 AN: 151966 Hom.: 838 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.108 AC: 26931 AN: 249322 Hom.: 1566 AF XY: 0.108 AC XY: 14641 AN XY: 135278

Gnomad AFR exome AF: 0.0962

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0769

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150748 AN: 1461624 Hom.: 8024 Cov.: 32 AF XY: 0.103 AC XY: 75211 AN XY: 727110

Gnomad4 AFR exome AF: 0.0988

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0843

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.0731

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.102 AC: 15525 AN: 152084 Hom.: 838 Cov.: 32 AF XY: 0.101 AC XY: 7510 AN XY: 74348

Gnomad4 AFR AF: 0.0949

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.119

Alfa AF: 0.110 Hom.: 711

Bravo AF: 0.107

TwinsUK AF: 0.107 AC: 397

ALSPAC AF: 0.108 AC: 418

ESP6500AA AF: 0.0960 AC: 372

ESP6500EA AF: 0.107 AC: 883

ExAC AF: 0.106 AC: 12809

Asia WGS AF: 0.101 AC: 352 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Porencephaly 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	11
Dann	Benign	0.80
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.28
Sift	Benign	0.44	T
Sift4G	Benign	0.25	T
Polyphen		0.0030	B
Vest4		0.051
MPC		0.73
ClinPred		0.0027	T
GERP RS		1.4
Varity_R		0.032
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs3803230; hg19: chr13-111119396; COSMIC: COSV64628379; COSMIC: COSV64628379;