19-40580787-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_138392.4(SHKBP1):​c.695C>T​(p.Pro232Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SHKBP1
NM_138392.4 missense

Scores

5
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.40
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHKBP1NM_138392.4 linkc.695C>T p.Pro232Leu missense_variant Exon 9 of 18 ENST00000291842.10 NP_612401.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHKBP1ENST00000291842.10 linkc.695C>T p.Pro232Leu missense_variant Exon 9 of 18 1 NM_138392.4 ENSP00000291842.4 Q8TBC3-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248878
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459070
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
725586
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

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.695C>T (p.P232L) alteration is located in exon 9 (coding exon 9) of the SHKBP1 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the proline (P) at amino acid position 232 to be replaced by a leucine (L). 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
Uncertain
0.54
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-9.7
D;.
REVEL
Benign
0.26
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.0050
B;.
Vest4
0.88
MutPred
0.64
Gain of MoRF binding (P = 0.0724);Gain of MoRF binding (P = 0.0724);
MVP
0.71
MPC
1.5
ClinPred
0.97
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.81
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs776073558; hg19: chr19-41086693; API