Genetic Variant FRG2:p.Arg257Thr (chr4-190025631-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001286820.2(FRG2):c.770G>C(p.Arg257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000083 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FRG2
NM_001286820.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.207

Publications

0 publications found

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]

FRG2 links:

ENSG00000297175 (HGNC:):

ENSG00000297175 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1105181).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286820.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRG2	NM_001286820.2	MANE Select	c.770G>C	p.Arg257Thr	missense	Exon 4 of 4	NP_001273749.1	Q64ET8-2
	FRG2	NM_001005217.4		c.767G>C	p.Arg256Thr	missense	Exon 4 of 4	NP_001005217.1	Q64ET8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRG2	ENST00000504750.6	TSL:1 MANE Select	c.770G>C	p.Arg257Thr	missense	Exon 4 of 4	ENSP00000424015.1	Q64ET8-2
FRG2	ENST00000378763.1	TSL:1	c.767G>C	p.Arg256Thr	missense	Exon 4 of 4	ENSP00000368039.1	Q64ET8-1
ENSG00000297175	ENST00000745955.1		n.270-2364C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000834

AC:

AN:

119884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000299

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000514

AC:

AN:

1168044

Hom.:

Cov.:

AF XY:

0.00000172

AC XY:

AN XY:

580314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27620

American (AMR)

AF:

0.00

AC:

AN:

31550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20966

East Asian (EAS)

AF:

0.0000287

AC:

AN:

34902

South Asian (SAS)

AF:

0.0000279

AC:

AN:

71684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3534

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

881728

Other (OTH)

AF:

0.0000601

AC:

AN:

49882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000833

AC:

AN:

119988

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

56752

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32086

American (AMR)

AF:

0.00

AC:

AN:

10978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

4118

South Asian (SAS)

AF:

0.000300

AC:

AN:

3336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56256

Other (OTH)

AF:

0.00

AC:

AN:

1508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.073

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.0022

M_CAP

Benign

0.0026

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

PhyloP100

-0.21

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.036

Sift

Uncertain

0.010

Sift4G

Uncertain

0.029

Polyphen

0.94

Vest4

0.17

MutPred

0.16

Loss of helix (P = 0.0444)

MVP

0.030

MPC

2.3

ClinPred

0.38

GERP RS

0.35

Varity_R

0.14

gMVP

0.012

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over