1-157767405-T-C

Variant names:

• chr1-157767405-T-C
• rs144781687
• NM_030764.4:c.988A>G

Variant summary

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

The NM_030764.4(FCRL2):​c.988A>G​(p.Ile330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: FCRL2 NM_030764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.903

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]

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=0.10760406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCRL2	NM_030764.4	c.988A>G	p.Ile330Val	missense_variant	Exon 6 of 12	ENST00000361516.8	NP_110391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCRL2	ENST00000361516.8	c.988A>G	p.Ile330Val	missense_variant	Exon 6 of 12	1	NM_030764.4	ENSP00000355157.3
FCRL2	ENST00000469986.1	c.229A>G	p.Ile77Val	missense_variant	Exon 1 of 2	1		ENSP00000417393.1
FCRL2	ENST00000368181.4	c.311-434A>G		intron_variant	Intron 3 of 7	1		ENSP00000357163.4
FCRL2	ENST00000368178.3	n.2906A>G		non_coding_transcript_exon_variant	Exon 1 of 7	1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251422 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135878

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

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: 0.0000369

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.988A>G (p.I330V) alteration is located in exon 6 (coding exon 6) of the FCRL2 gene. This alteration results from a A to G substitution at nucleotide position 988, causing the isoleucine (I) at amino acid position 330 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.69	T;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.047
Sift	Benign	0.071	T;T
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;.
Vest4		0.41
MVP		0.16
MPC		0.22
ClinPred		0.27	T
GERP RS		1.6
Varity_R		0.036
gMVP		0.072

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: rs144781687; hg19: chr1-157737195;