rs7990383

Variant names:

• chr13-110458888-G-A
• rs7990383
• NM_001846.4:c.1550G>A

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.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. 14/21 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:7
• Conservation: PhyloP100: -1.28
• Publications: 36 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-AS2 (HGNC:39849): (COL4A2 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 311129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1550G>A	p.Arg517Lys	missense_variant	Exon 22 of 48	ENST00000360467.7	NP_001837.2
COL4A2-AS2	NR_171022.1	n.266-602C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1550G>A	p.Arg517Lys	missense_variant	Exon 22 of 48	5	NM_001846.4	ENSP00000353654.5

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

GnomAD2 exomes AF: 0.524 AC: 127365 AN: 243276 AF XY: 0.527

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 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

African (AFR) AF: 0.694 AC: 23059 AN: 33204

American (AMR) AF: 0.397 AC: 17421 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 17069 AN: 25696

East Asian (EAS) AF: 0.184 AC: 7279 AN: 39516

South Asian (SAS) AF: 0.479 AC: 40990 AN: 85654

European-Finnish (FIN) AF: 0.445 AC: 23689 AN: 53180

Middle Eastern (MID) AF: 0.675 AC: 3864 AN: 5726

European-Non Finnish (NFE) AF: 0.606 AC: 671854 AN: 1109348

Other (OTH) AF: 0.578 AC: 34747 AN: 60100

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

African (AFR) AF: 0.683 AC: 28340 AN: 41464

American (AMR) AF: 0.492 AC: 7520 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2358 AN: 3472

East Asian (EAS) AF: 0.226 AC: 1163 AN: 5156

South Asian (SAS) AF: 0.458 AC: 2201 AN: 4810

European-Finnish (FIN) AF: 0.429 AC: 4532 AN: 10572

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40949 AN: 67930

Other (OTH) AF: 0.585 AC: 1233 AN: 2106

Alfa AF: 0.598 Hom.: 29070

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Porencephaly 2 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.065
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
PhyloP100		-1.3
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
Mutation Taster		=99/1	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: rs7990383; hg19: chr13-111111235; COSMIC: COSV64624781; COSMIC: COSV64624781;