X-101353935-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000061.3(BTK):c.1685G>C(p.Arg562Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
BTK
NM_000061.3 missense
NM_000061.3 missense
Scores
6
6
1
Clinical Significance
Conservation
PhyloP100: 6.13
Genes affected
BTK (HGNC:1133): (Bruton tyrosine kinase) The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000061.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-101353935-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2431408.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant where missense usually causes diseases, BTK
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant X-101353935-C-G is Pathogenic according to our data. Variant chrX-101353935-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11394.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101353935-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1685G>C | p.Arg562Pro | missense_variant | 17/19 | ENST00000308731.8 | |
BTK | NM_001287344.2 | c.1787G>C | p.Arg596Pro | missense_variant | 17/19 | ||
BTK | NM_001287345.2 | c.1157G>C | p.Arg386Pro | missense_variant | 15/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1685G>C | p.Arg562Pro | missense_variant | 17/19 | 1 | NM_000061.3 | P3 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2015 | The R562P missense variant in the BTK gene has been reported previously in association withX-linked agammaglobulinemia (Vihinen et al., 1994; Curtis et al., 2000). This pathogenic variant occurs in the protein kinasedomain of the BTK protein near other residues with reported pathogenic variants (Vihinen et al.,1994). R562P impairs the kinase activity of the resulting protein despite a lack of effect on proteinlevels (Maniar et al., 1995). Additionally, the R562P variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. Therefore, we interpret R562P as a pathogenic variant. - |
X-linked agammaglobulinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 31, 2000 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;D;.;D
Vest4
MutPred
Gain of catalytic residue at W563 (P = 0.0184);.;.;Gain of catalytic residue at W563 (P = 0.0184);
MVP
MPC
3.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at