4-190025732-C-A

Variant names:

• chr4-190025732-C-A
• rs1338060785
• NM_001286820.2:c.669G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286820.2(FRG2):​c.669G>T​(p.Gln223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRG2 NM_001286820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.134

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19211718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRG2	NM_001286820.2	c.669G>T	p.Gln223His	missense_variant	Exon 4 of 4	ENST00000504750.6	NP_001273749.1
FRG2	NM_001005217.4	c.666G>T	p.Gln222His	missense_variant	Exon 4 of 4		NP_001005217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRG2	ENST00000504750.6	c.669G>T	p.Gln223His	missense_variant	Exon 4 of 4	1	NM_001286820.2	ENSP00000424015.1
FRG2	ENST00000378763.1	c.666G>T	p.Gln222His	missense_variant	Exon 4 of 4	1		ENSP00000368039.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000267 AC: 39 AN: 1459032 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 725554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 21

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.666G>T (p.Q222H) alteration is located in exon 4 (coding exon 4) of the FRG2 gene. This alteration results from a G to T substitution at nucleotide position 666, causing the glutamine (Q) at amino acid position 222 to be replaced by a histidine (H). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.0042	N
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	.;L
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.067
Sift	Benign	0.25	T;T
Sift4G	Uncertain	0.043	D;D
Polyphen		0.97	.;D
Vest4		0.42
MutPred		0.40		.;Gain of sheet (P = 0.0125);
MVP		0.048
MPC		2.8
ClinPred		0.35	T
GERP RS		0.35
Varity_R		0.12
gMVP		0.047

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

Other links and lift over

dbSNP: rs1338060785; hg19: chr4-190946887;