Genetic Variant FCRL2:p.Ala438Pro (chr1-157748956-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030764.4(FCRL2):c.1312G>C(p.Ala438Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FCRL2
NM_030764.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00200

Variant links:

Genes affected

FCRL2 (HGNC:14875): (Fc receptor like 2) This gene encodes a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1. The encoded protein has four extracellular C2-type immunoglobulin domains, a transmembrane domain and a cytoplasmic domain that contains one immunoreceptor-tyrosine activation motif and two immunoreceptor-tyrosine inhibitory motifs. This protein may be a prognostic marker for chronic lymphocytic leukemia. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Apr 2009]

FCRL2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042804748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCRL2	NM_030764.4 link	c.1312G>C	p.Ala438Pro	missense_variant	Exon 9 of 12	ENST00000361516.8	NP_110391.2	Q96LA5-1B4E0W2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FCRL2	ENST00000361516.8 link	c.1312G>C	p.Ala438Pro	missense_variant	Exon 9 of 12	1	NM_030764.4	ENSP00000355157.3	Q96LA5-1
FCRL2	ENST00000368181.4 link	c.460G>C	p.Ala154Pro	missense_variant	Exon 6 of 8	1		ENSP00000357163.4	Q96LA5-5
FCRL2	ENST00000368178.3 link	n.3230G>C		non_coding_transcript_exon_variant	Exon 4 of 7	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250968

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461378

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727032

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312G>C (p.A438P) alteration is located in exon 9 (coding exon 9) of the FCRL2 gene. This alteration results from a G to C substitution at nucleotide position 1312, causing the alanine (A) at amino acid position 438 to be replaced by a proline (P). 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

0.080

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.51

DANN

Benign

0.81

DEOGEN2

Benign

0.0079

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.31

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.49

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.32

N;N

REVEL

Benign

0.018

Sift

Benign

0.68

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.16

Gain of glycosylation at A438 (P = 0.0158);.;

MVP

0.12

MPC

0.042

ClinPred

0.020

GERP RS

0.96

Varity_R

0.037

gMVP

0.065

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