19-7690180-T-C

Variant names:

• chr19-7690180-T-C
• NM_001220500.2:c.707A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001220500.2(FCER2):​c.707A>G​(p.Asp236Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FCER2 NM_001220500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

FCER2 (HGNC:3612): (Fc epsilon receptor II) The protein encoded by this gene is a B-cell specific antigen, and a low-affinity receptor for IgE. It has essential roles in B cell growth and differentiation, and the regulation of IgE production. This protein also exists as a soluble secreted form, then functioning as a potent mitogenic growth factor. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCER2	NM_001220500.2	c.707A>G	p.Asp236Gly	missense_variant	Exon 10 of 11	ENST00000597921.6	NP_001207429.1
FCER2	NM_002002.5	c.707A>G	p.Asp236Gly	missense_variant	Exon 10 of 11		NP_001993.2
FCER2	NM_001207019.3	c.704A>G	p.Asp235Gly	missense_variant	Exon 9 of 10		NP_001193948.2
FCER2	XM_005272462.5	c.707A>G	p.Asp236Gly	missense_variant	Exon 10 of 11		XP_005272519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCER2	ENST00000597921.6	c.707A>G	p.Asp236Gly	missense_variant	Exon 10 of 11	1	NM_001220500.2	ENSP00000471974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.707A>G (p.D236G) alteration is located in exon 10 (coding exon 9) of the FCER2 gene. This alteration results from a A to G substitution at nucleotide position 707, causing the aspartic acid (D) at amino acid position 236 to be replaced by a glycine (G). 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	0.66
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.29	.;T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.64	T;.;T
M_CAP	Benign	0.0083	T
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.2	.;M;M
PhyloP100		1.0
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.7	D;D;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.77
MutPred		0.92		.;Gain of catalytic residue at G237 (P = 0.1553);Gain of catalytic residue at G237 (P = 0.1553);
MVP		0.68
MPC		0.44
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.81
gMVP		0.64
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr19-7755066;