chr4-190025758-G-A

Variant names:

• chr4-190025758-G-A
• rs1158149554
• NM_001286820.2:c.643C>T

Variant summary

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

The NM_001286820.2(FRG2):​c.643C>T​(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.000040 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRG2 NM_001286820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.869
• Publications: 0 publications found

Genes affected

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

ENSG00000297175 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.10832313).

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.643C>T	p.Arg215Trp	missense	Exon 4 of 4	NP_001273749.1	Q64ET8-2
	FRG2	NM_001005217.4		c.640C>T	p.Arg214Trp	missense	Exon 4 of 4	NP_001005217.1	Q64ET8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRG2	ENST00000504750.6	TSL:1 MANE Select	c.643C>T	p.Arg215Trp	missense	Exon 4 of 4	ENSP00000424015.1	Q64ET8-2
	FRG2	ENST00000378763.1	TSL:1	c.640C>T	p.Arg214Trp	missense	Exon 4 of 4	ENSP00000368039.1	Q64ET8-1
	ENSG00000297175	ENST00000745955.1		n.270-2237G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000404 AC: 6 AN: 148496 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

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: 0.0000746

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000685 AC: 100 AN: 1459988 Hom.: 0 Cov.: 31 AF XY: 0.0000730 AC XY: 53 AN XY: 726056

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

African (AFR) AF: 0.0000598 AC: 2 AN: 33454

American (AMR) AF: 0.000560 AC: 25 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1110644

Other (OTH) AF: 0.0000829 AC: 5 AN: 60294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000404 AC: 6 AN: 148496 Hom.: 0 Cov.: 22 AF XY: 0.0000277 AC XY: 2 AN XY: 72176

African (AFR) AF: 0.00 AC: 0 AN: 40320

American (AMR) AF: 0.0000677 AC: 1 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4894

South Asian (SAS) AF: 0.00 AC: 0 AN: 4592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000746 AC: 5 AN: 67018

Other (OTH) AF: 0.00 AC: 0 AN: 1994

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.28
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0048	N
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.87
PROVEAN	Benign	0.99	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.43		Loss of solvent accessibility (P = 0.0079)
MVP		0.072
MPC		1.7
ClinPred		0.44	T
GERP RS		-0.59
Varity_R		0.13
gMVP		0.031
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1158149554; hg19: chr4-190946913; COSMIC: COSV66459783; COSMIC: COSV66459783;