4-190025763-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001286820.2(FRG2):​c.638G>A​(p.Arg213Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 22)
Exomes 𝑓: 0.000055 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FRG2
NM_001286820.2 missense

Scores

17

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.41
Variant links:
Genes affected
FRG2 (HGNC:19136): (FSHD region gene 2) Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0423162).
BP6
Variant 4-190025763-C-T is Benign according to our data. Variant chr4-190025763-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2318737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRG2NM_001286820.2 linkc.638G>A p.Arg213Gln missense_variant Exon 4 of 4 ENST00000504750.6 NP_001273749.1 Q64ET8-2
FRG2NM_001005217.4 linkc.635G>A p.Arg212Gln missense_variant Exon 4 of 4 NP_001005217.1 Q64ET8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRG2ENST00000504750.6 linkc.638G>A p.Arg213Gln missense_variant Exon 4 of 4 1 NM_001286820.2 ENSP00000424015.1 Q64ET8-2
FRG2ENST00000378763.1 linkc.635G>A p.Arg212Gln missense_variant Exon 4 of 4 1 ENSP00000368039.1 Q64ET8-1

Frequencies

GnomAD3 genomes
AF:
0.000107
AC:
16
AN:
148978
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.000297
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000672
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000447
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000548
AC:
80
AN:
1460686
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
726506
show subpopulations
Gnomad4 AFR exome
AF:
0.000628
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000365
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000114
AC:
17
AN:
149082
Hom.:
0
Cov.:
22
AF XY:
0.0000689
AC XY:
5
AN XY:
72576
show subpopulations
Gnomad4 AFR
AF:
0.000320
Gnomad4 AMR
AF:
0.0000672
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000447
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 28, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.063
DANN
Benign
0.21
DEOGEN2
Benign
0.010
.;T
Eigen
Benign
-2.0
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.00037
N
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.0
.;N
PROVEAN
Benign
1.2
N;N
REVEL
Benign
0.013
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
.;B
Vest4
0.074
MutPred
0.22
.;Loss of methylation at R214 (P = 0.0648);
MVP
0.014
MPC
1.8
ClinPred
0.053
T
GERP RS
-0.59
Varity_R
0.040
gMVP
0.0029

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: rs1254649094; hg19: chr4-190946918; API