rs139956304

Variant names:

• chr1-157746774-C-A
• rs139956304
• NM_030764.4:c.1489G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-157746774-C-A
• chr1-157746774-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030764.4(FCRL2):​c.1489G>T​(p.Asp497Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D497N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FCRL2 NM_030764.4 missense, splice_region
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030764.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCRL2	NM_030764.4	MANE Select	c.1489G>T	p.Asp497Tyr	missense splice_region	Exon 12 of 12	NP_110391.2
	FCRL2	NM_001159488.2		c.1308G>T	p.Arg436Ser	missense splice_region	Exon 9 of 9	NP_001152960.1	B4DVJ9
	FCRL2	NR_125358.2		n.630G>T		splice_region non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCRL2	ENST00000361516.8	TSL:1 MANE Select	c.1489G>T	p.Asp497Tyr	missense splice_region	Exon 12 of 12	ENSP00000355157.3	Q96LA5-1
	FCRL2	ENST00000368181.4	TSL:1	c.571G>T	p.Asp191Tyr	missense splice_region	Exon 8 of 8	ENSP00000357163.4	Q96LA5-5
	FCRL2	ENST00000368178.3	TSL:1	n.3407G>T		splice_region non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.24
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.14
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.40		Loss of disorder (P = 0.0172)
MVP		0.30
MPC		0.15
ClinPred		0.80	D
GERP RS		3.4
Varity_R		0.12
gMVP		0.22
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139956304; hg19: chr1-157716564; COSMIC: COSV100829905;