rs1739516446

Variant names:

• chr4-190025925-C-T
• rs1739516446
• NM_001286820.2:c.476G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286820.2(FRG2):​c.476G>A​(p.Arg159Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: FRG2 NM_001286820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.91
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059031606).

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.476G>A	p.Arg159Gln	missense	Exon 4 of 4	NP_001273749.1	Q64ET8-2
	FRG2	NM_001005217.4		c.473G>A	p.Arg158Gln	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.476G>A	p.Arg159Gln	missense	Exon 4 of 4	ENSP00000424015.1	Q64ET8-2
	FRG2	ENST00000378763.1	TSL:1	c.473G>A	p.Arg158Gln	missense	Exon 4 of 4	ENSP00000368039.1	Q64ET8-1
	ENSG00000297175	ENST00000745955.1		n.270-2070C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111842

Other (OTH) AF: 0.0000331 AC: 2 AN: 60378

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 22 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.62
DANN	Benign	0.85
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00083	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.9
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.017
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.022	B
Vest4		0.057
MutPred		0.21		Gain of glycosylation at S161 (P = 0.0316)
MVP		0.030
MPC		1.8
ClinPred		0.092	T
GERP RS		0.35
Varity_R		0.040
gMVP		0.0053
Mutation Taster		=100/0	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: rs1739516446; hg19: chr4-190947080;