Genetic Variant FRG2:p.Lys54Thr (chr4-190027044-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001286820.2(FRG2):c.161A>C(p.Lys54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000042 ( 1 hom., cov: 15)

Exomes 𝑓: 0.0000082 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

FRG2
NM_001286820.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.737

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09786421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRG2	NM_001286820.2 link	c.161A>C	p.Lys54Thr	missense_variant	Exon 1 of 4	ENST00000504750.6	NP_001273749.1	Q64ET8-2
FRG2	NM_001005217.4 link	c.161A>C	p.Lys54Thr	missense_variant	Exon 1 of 4		NP_001005217.1	Q64ET8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRG2	ENST00000504750.6 link	c.161A>C	p.Lys54Thr	missense_variant	Exon 1 of 4	1	NM_001286820.2	ENSP00000424015.1		Q64ET8-2
FRG2	ENST00000378763.1 link	c.161A>C	p.Lys54Thr	missense_variant	Exon 1 of 4	1		ENSP00000368039.1		Q64ET8-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

95130

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000699

Gnomad OTH

AF:

0.000773

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000819

AC:

AN:

1343636

Hom.:

Cov.:

AF XY:

0.00000448

AC XY:

AN XY:

669404

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000155

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.69e-7

Gnomad4 OTH exome

AF:

0.0000742

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000420

AC:

AN:

95130

Hom.:

Cov.:

AF XY:

0.0000436

AC XY:

AN XY:

45886

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000699

Gnomad4 OTH

AF:

0.000773

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161A>C (p.K54T) alteration is located in exon 1 (coding exon 1) of the FRG2 gene. This alteration results from a A to C substitution at nucleotide position 161, causing the lysine (K) at amino acid position 54 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.5

DANN

Benign

0.82

DEOGEN2

Benign

0.024

.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.039

M_CAP

Benign

0.0017

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.053

Sift

Uncertain

0.024

D;D

Sift4G

Benign

0.25

T;T

Polyphen

0.59

.;P

Vest4

0.25

MutPred

0.24

Loss of ubiquitination at K54 (P = 6e-04);Loss of ubiquitination at K54 (P = 6e-04);

MVP

0.014

MPC

2.2

ClinPred

0.28

GERP RS

0.35

Varity_R

0.065

gMVP

0.0090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over