Genetic Variant FRG2:p.Pro244Leu (chr4-190025670-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001286820.2(FRG2):c.731C>T(p.Pro244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,388,718 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 18)

Exomes 𝑓: 0.011 ( 147 hom. )

Failed GnomAD Quality Control

Consequence

FRG2
NM_001286820.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.169

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23275197).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.011 (15240/1388718) while in subpopulation AMR AF = 0.0319 (1227/38466). AF 95% confidence interval is 0.0304. There are 147 homozygotes in GnomAdExome4. There are 7489 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 147 AR gene

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.731C>T	p.Pro244Leu	missense	Exon 4 of 4	NP_001273749.1	Q64ET8-2
	FRG2	NM_001005217.4		c.728C>T	p.Pro243Leu	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.731C>T	p.Pro244Leu	missense	Exon 4 of 4	ENSP00000424015.1	Q64ET8-2
FRG2	ENST00000378763.1	TSL:1	c.728C>T	p.Pro243Leu	missense	Exon 4 of 4	ENSP00000368039.1	Q64ET8-1
ENSG00000297175	ENST00000745955.1		n.270-2325G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1483

AN:

129540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00173

Gnomad AMI

AF:

0.0638

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.0172

Gnomad EAS

AF:

0.000231

Gnomad SAS

AF:

0.00299

Gnomad FIN

AF:

0.0481

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.00975

Gnomad OTH

AF:

0.0111

GnomAD4 exome

AF:

0.0110

AC:

15240

AN:

1388718

Hom.:

147

Cov.:

AF XY:

0.0109

AC XY:

7489

AN XY:

687710

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

31896

American (AMR)

AF:

0.0319

AC:

1227

AN:

38466

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

445

AN:

24540

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37768

South Asian (SAS)

AF:

0.00628

AC:

518

AN:

82426

European-Finnish (FIN)

AF:

0.0512

AC:

2611

AN:

50984

Middle Eastern (MID)

AF:

0.00594

AC:

AN:

4380

European-Non Finnish (NFE)

AF:

0.00923

AC:

9789

AN:

1060744

Other (OTH)

AF:

0.0103

AC:

590

AN:

57514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

582

1165

1747

2330

2912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.0114

AC:

1480

AN:

129658

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

783

AN XY:

61952

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

34748

American (AMR)

AF:

0.0235

AC:

288

AN:

12232

Ashkenazi Jewish (ASJ)

AF:

0.0172

AC:

AN:

3140

East Asian (EAS)

AF:

0.000231

AC:

AN:

4320

South Asian (SAS)

AF:

0.00299

AC:

AN:

3674

European-Finnish (FIN)

AF:

0.0481

AC:

405

AN:

8424

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00975

AC:

589

AN:

60412

Other (OTH)

AF:

0.0110

AC:

AN:

1642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00953

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

0.24

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.0067

M_CAP

Benign

0.0065

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.90

PhyloP100

-0.17

PROVEAN

Pathogenic

-6.6

REVEL

Benign

0.091

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.35

MutPred

0.44

Loss of loop (P = 0.0145)

MVP

0.29

MPC

2.6

ClinPred

0.94

GERP RS

0.11

Varity_R

0.072

gMVP

0.026

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over