rs9583500

Variant names:

• chr13-110469273-C-T
• rs9583500
• NM_001846.4:c.2152C>T

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.2152C>T​(p.Pro718Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,602,244 control chromosomes in the GnomAD database, including 34,521 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 0.23 (4385 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30136 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.924
• Publications: 25 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 (MetaRNN=0.0032528043).
• BP6: Variant 13-110469273-C-T is Benign according to our data. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110469273-C-T is described in CliVar as Benign. Clinvar id is 311145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2152C>T	p.Pro718Ser	missense_variant	Exon 28 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2152C>T	p.Pro718Ser	missense_variant	Exon 28 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34351 AN: 151944 Hom.: 4379 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.0180

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.175 AC: 39604 AN: 226146 AF XY: 0.173

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.196 AC: 284844 AN: 1450182 Hom.: 30136 Cov.: 33 AF XY: 0.194 AC XY: 139485 AN XY: 719896

African (AFR) AF: 0.329 AC: 10980 AN: 33332

American (AMR) AF: 0.127 AC: 5493 AN: 43372

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7855 AN: 25826

East Asian (EAS) AF: 0.0107 AC: 422 AN: 39496

South Asian (SAS) AF: 0.110 AC: 9213 AN: 83592

European-Finnish (FIN) AF: 0.180 AC: 9492 AN: 52620

Middle Eastern (MID) AF: 0.326 AC: 1841 AN: 5642

European-Non Finnish (NFE) AF: 0.205 AC: 227256 AN: 1106414

Other (OTH) AF: 0.205 AC: 12292 AN: 59888

GnomAD4 genome AF: 0.226 AC: 34403 AN: 152062 Hom.: 4385 Cov.: 32 AF XY: 0.219 AC XY: 16269 AN XY: 74330

African (AFR) AF: 0.323 AC: 13412 AN: 41462

American (AMR) AF: 0.188 AC: 2870 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1067 AN: 3466

East Asian (EAS) AF: 0.0180 AC: 93 AN: 5160

South Asian (SAS) AF: 0.103 AC: 495 AN: 4818

European-Finnish (FIN) AF: 0.174 AC: 1838 AN: 10582

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13782 AN: 67970

Other (OTH) AF: 0.240 AC: 506 AN: 2110

Alfa AF: 0.211 Hom.: 7894

Bravo AF: 0.234

TwinsUK AF: 0.194 AC: 721

ALSPAC AF: 0.203 AC: 784

ESP6500AA AF: 0.301 AC: 1150

ESP6500EA AF: 0.199 AC: 1637

ExAC AF: 0.171 AC: 20572

Asia WGS AF: 0.105 AC: 368 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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	0.083
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.92
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.30
Sift	Benign	0.83	T
Sift4G	Benign	0.73	T
Polyphen		0.21	B
Vest4		0.059
MPC		0.32
ClinPred		0.015	T
GERP RS		5.6
Varity_R		0.048
gMVP		0.14
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: rs9583500; hg19: chr13-111121620;