10-96227509-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013314.4(BLNK):​c.262G>T​(p.Ala88Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

BLNK
NM_013314.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38
Variant links:
Genes affected
BLNK (HGNC:14211): (B cell linker) This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.1132105).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLNKNM_013314.4 linkc.262G>T p.Ala88Ser missense_variant Exon 5 of 17 ENST00000224337.10 NP_037446.1 Q8WV28-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLNKENST00000224337.10 linkc.262G>T p.Ala88Ser missense_variant Exon 5 of 17 1 NM_013314.4 ENSP00000224337.6 Q8WV28-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461836
Hom.:
0
Cov.:
37
AF XY:
0.00000413
AC XY:
3
AN XY:
727224
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:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Uncertain:1
Mar 14, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with BLNK-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 88 of the BLNK protein (p.Ala88Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;.;T;.
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.85
D;D;T;D
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;L;.;L
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.1
N;N;N;N
REVEL
Benign
0.053
Sift
Benign
0.21
T;T;T;T
Sift4G
Benign
0.65
T;T;T;T
Polyphen
0.0020
B;B;B;.
Vest4
0.12
MutPred
0.12
Gain of phosphorylation at A88 (P = 0.012);Gain of phosphorylation at A88 (P = 0.012);Gain of phosphorylation at A88 (P = 0.012);Gain of phosphorylation at A88 (P = 0.012);
MVP
0.45
MPC
0.32
ClinPred
0.20
T
GERP RS
5.8
Varity_R
0.051
gMVP
0.086

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.

Other links and lift over

dbSNP: rs144903484; hg19: chr10-97987265; API