4-190026440-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.278G>A​(p.Arg93Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 142,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R93P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 22)
Exomes 𝑓: 0.00012 ( 4 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: -0.398
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=0.008796185).
BP6
Variant 4-190026440-C-T is Benign according to our data. Variant chr4-190026440-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2270450.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.278G>A p.Arg93Gln missense_variant Exon 3 of 4 ENST00000504750.6 NP_001273749.1 Q64ET8-2
FRG2NM_001005217.4 linkc.275G>A p.Arg92Gln missense_variant Exon 3 of 4 NP_001005217.1 Q64ET8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRG2ENST00000504750.6 linkc.278G>A p.Arg93Gln missense_variant Exon 3 of 4 1 NM_001286820.2 ENSP00000424015.1 Q64ET8-2
FRG2ENST00000378763.1 linkc.275G>A p.Arg92Gln missense_variant Exon 3 of 4 1 ENSP00000368039.1 Q64ET8-1

Frequencies

GnomAD3 genomes
AF:
0.000476
AC:
68
AN:
142992
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.00152
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000693
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:
0.000167
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000214
AC:
17
AN:
79390
Hom.:
0
AF XY:
0.000234
AC XY:
9
AN XY:
38450
show subpopulations
Gnomad AFR exome
AF:
0.00151
Gnomad AMR exome
AF:
0.000179
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000155
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000125
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000119
AC:
172
AN:
1450304
Hom.:
4
Cov.:
30
AF XY:
0.000121
AC XY:
87
AN XY:
721936
show subpopulations
Gnomad4 AFR exome
AF:
0.000989
Gnomad4 AMR exome
AF:
0.0000899
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000114
Gnomad4 OTH exome
AF:
0.000150
GnomAD4 genome
AF:
0.000476
AC:
68
AN:
142992
Hom.:
0
Cov.:
22
AF XY:
0.000288
AC XY:
20
AN XY:
69488
show subpopulations
Gnomad4 AFR
AF:
0.00152
Gnomad4 AMR
AF:
0.0000693
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000167
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000169
Hom.:
0
ESP6500AA
AF:
0.00100
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000131
AC:
7

ClinVar

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

Submissions by phenotype

not specified Benign:1
Sep 06, 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
0.071
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
2.5
DANN
Benign
0.41
DEOGEN2
Benign
0.0065
.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.013
N
M_CAP
Benign
0.0018
T
MetaRNN
Benign
0.0088
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
.;N
PROVEAN
Benign
0.11
N;N
REVEL
Benign
0.041
Sift
Benign
0.36
T;T
Sift4G
Benign
0.56
T;T
Polyphen
0.0010
.;B
Vest4
0.18
MVP
0.014
MPC
1.8
ClinPred
0.0076
T
GERP RS
0.35
Varity_R
0.052
gMVP
0.0071

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs377567180; hg19: chr4-190947595; API