rs7990383

chr13-110458888-G-A

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.1550G>A(p.Arg517Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 1,608,274 control chromosomes in the GnomAD database, including 275,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27089 hom., cov: 31)
  • Exomes 𝑓: 0.58 (248494 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.28

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-AS2 (HGNC:39849): (COL4A2 antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3651943E-5).
• BP6: Variant 13-110458888-G-A is Benign according to our data. Variant chr13-110458888-G-A is described in ClinVar as [Benign]. Clinvar id is 311129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110458888-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.1550G>A	p.Arg517Lys	missense_variant	22/48	ENST00000360467.7
COL4A2-AS2	NR_171022.1	n.266-602C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.1550G>A	p.Arg517Lys	missense_variant	22/48	5	NM_001846.4	P1
COL4A2-AS2	ENST00000458403.2	n.266-602C>T		intron_variant, non_coding_transcript_variant		2
COL4A2	ENST00000617564.2	c.809G>A	p.Arg270Lys	missense_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89041 AN: 151888 Hom.: 27056 Cov.: 31

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.524 AC: 127365 AN: 243276 Hom.: 35306 AF XY: 0.527 AC XY: 69711 AN XY: 132158

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.602

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.577 AC: 839972 AN: 1456268 Hom.: 248494 Cov.: 52 AF XY: 0.575 AC XY: 416327 AN XY: 724358

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.664

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.606

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.586 AC: 89128 AN: 152006 Hom.: 27089 Cov.: 31 AF XY: 0.574 AC XY: 42615 AN XY: 74262

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.458

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.585

Alfa AF: 0.604 Hom.: 18910

Bravo AF: 0.594

TwinsUK AF: 0.602 AC: 2234

ALSPAC AF: 0.610 AC: 2350

ESP6500AA AF: 0.694 AC: 2674

ESP6500EA AF: 0.607 AC: 5007

ExAC AF: 0.532 AC: 64271

Asia WGS AF: 0.376 AC: 1310 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

Porencephaly 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.044
Dann	Benign	0.50
DEOGEN2	Benign	0.29	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.090	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.45
ClinPred		0.022	T
GERP RS		-10
Varity_R		0.083
gMVP		0.35

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: rs7990383; hg19: chr13-111111235; COSMIC: COSV64624781; COSMIC: COSV64624781;