rs128622212
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_000061.3(BTK):c.1955T>C(p.Leu652Pro) 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 (no stars).
Frequency
Genomes: not found (cov: 22)
Consequence
BTK
NM_000061.3 missense
NM_000061.3 missense
Scores
5
5
5
Clinical Significance
Conservation
PhyloP100: 4.59
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a helix (size 13) in uniprot entity BTK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000061.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, BTK
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.831
PP5
?
Variant X-101349910-A-G is Pathogenic according to our data. Variant chrX-101349910-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11392.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101349910-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1955T>C | p.Leu652Pro | missense_variant | 19/19 | ENST00000308731.8 | |
BTK | NM_001287344.2 | c.2057T>C | p.Leu686Pro | missense_variant | 19/19 | ||
BTK | NM_001287345.2 | c.1427T>C | p.Leu476Pro | missense_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1955T>C | p.Leu652Pro | missense_variant | 19/19 | 1 | NM_000061.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
X-linked agammaglobulinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1994 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Benign
T;T;T
Polyphen
D;.;P
Vest4
MutPred
0.66
.;.;Loss of stability (P = 0.0032);
MVP
MPC
2.4
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