19-40580347-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138392.4(SHKBP1):​c.424C>T​(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SHKBP1
NM_138392.4 missense

Scores

1
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.935
Variant links:
Genes affected
SHKBP1 (HGNC:19214): (SH3KBP1 binding protein 1) Enables identical protein binding activity. Predicted to be involved in positive regulation of epidermal growth factor receptor signaling pathway. Predicted to be located in lysosome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3437509).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHKBP1NM_138392.4 linkc.424C>T p.Arg142Trp missense_variant Exon 7 of 18 ENST00000291842.10 NP_612401.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHKBP1ENST00000291842.10 linkc.424C>T p.Arg142Trp missense_variant Exon 7 of 18 1 NM_138392.4 ENSP00000291842.4 Q8TBC3-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152218
Hom.:
0
Cov.:
31
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250790
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135576
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461726
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152218
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.424C>T (p.R142W) alteration is located in exon 7 (coding exon 7) of the SHKBP1 gene. This alteration results from a C to T substitution at nucleotide position 424, causing the arginine (R) at amino acid position 142 to be replaced by a tryptophan (W). 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
0.28
BayesDel_addAF
Benign
0.0023
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.25
T;T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.037
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.34
T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
1.5
L;.;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.7
D;.;.
REVEL
Benign
0.19
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
0.072
B;.;.
Vest4
0.80
MutPred
0.48
Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);.;
MVP
0.50
MPC
1.3
ClinPred
0.91
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.62

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: rs373689117; hg19: chr19-41086253; COSMIC: COSV52539645; COSMIC: COSV52539645; API