chr1-157767497-C-T

Variant names:

• chr1-157767497-C-T
• rs144215277
• NM_030764.4:c.896G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030764.4(FCRL2):​c.896G>A​(p.Arg299His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: FCRL2 NM_030764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23

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 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=0.056158543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCRL2	NM_030764.4	c.896G>A	p.Arg299His	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.896G>A	p.Arg299His	missense_variant	Exon 6 of 12	1	NM_030764.4	ENSP00000355157.3
FCRL2	ENST00000469986.1	c.137G>A	p.Arg46His	missense_variant	Exon 1 of 2	1		ENSP00000417393.1
FCRL2	ENST00000368181.4	c.311-526G>A		intron_variant	Intron 3 of 7	1		ENSP00000357163.4
FCRL2	ENST00000368178.3	n.2814G>A		non_coding_transcript_exon_variant	Exon 1 of 7	1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000918 AC: 23 AN: 250606 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135524

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74338

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000444 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.896G>A (p.R299H) alteration is located in exon 6 (coding exon 6) of the FCRL2 gene. This alteration results from a G to A substitution at nucleotide position 896, causing the arginine (R) at amino acid position 299 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	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.9
DANN	Benign	0.85
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N;D
REVEL	Benign	0.024
Sift	Benign	0.22	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.35	B;.
Vest4		0.074
MVP		0.11
MPC		0.044
ClinPred		0.025	T
GERP RS		-2.9
Varity_R		0.025
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs144215277; hg19: chr1-157737287; COSMIC: COSV63834708; COSMIC: COSV63834708;