rs9583500

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/20 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

Scores

2
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.924
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 ClinVar 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 Lovd as [Benign].
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/exons MANE Protein UniProt
COL4A2NM_001846.4 linkuse as main transcriptc.2152C>T p.Pro718Ser missense_variant 28/48 ENST00000360467.7 NP_001837.2 P08572A0A024RDW8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A2ENST00000360467.7 linkuse as main transcriptc.2152C>T p.Pro718Ser missense_variant 28/485 NM_001846.4 ENSP00000353654.5 P08572
COL4A2ENST00000494852.2 linkuse as main transcriptc.70C>T p.Pro24Ser missense_variant 2/43 ENSP00000497664.2 A0A3B3IT80

Frequencies

GnomAD3 genomes
AF:
0.226
AC:
34351
AN:
151944
Hom.:
4379
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.175
AC:
39604
AN:
226146
Hom.:
4142
AF XY:
0.173
AC XY:
21189
AN XY:
122436
show subpopulations
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 SAS exome
AF:
0.111
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
show subpopulations
Gnomad4 AFR exome
AF:
0.329
Gnomad4 AMR exome
AF:
0.127
Gnomad4 ASJ exome
AF:
0.304
Gnomad4 EAS exome
AF:
0.0107
Gnomad4 SAS exome
AF:
0.110
Gnomad4 FIN exome
AF:
0.180
Gnomad4 NFE exome
AF:
0.205
Gnomad4 OTH exome
AF:
0.205
GnomAD4 genome
AF:
0.226
AC:
34403
AN:
152062
Hom.:
4385
Cov.:
32
AF XY:
0.219
AC XY:
16269
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.323
Gnomad4 AMR
AF:
0.188
Gnomad4 ASJ
AF:
0.308
Gnomad4 EAS
AF:
0.0180
Gnomad4 SAS
AF:
0.103
Gnomad4 FIN
AF:
0.174
Gnomad4 NFE
AF:
0.203
Gnomad4 OTH
AF:
0.240
Alfa
AF:
0.211
Hom.:
6103
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
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 24, 2018This 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
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs9583500; hg19: chr13-111121620; API