5-148335627-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040433.2(SPINK9):​c.14C>G​(p.Ala5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

SPINK9
NM_001040433.2 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.133
Variant links:
Genes affected
SPINK9 (HGNC:32951): (serine peptidase inhibitor Kazal type 9) The protein encoded by this gene is a Kazal-type serine protease inhibitor that appears to specifically target kallikrein-related peptidase 5 (KLK5) in the palmo-plantar epidermis. KLK5 is an important initiator of skin desquamation, so the encoded protease inhibitor may regulate skin differentiation in the palms of hands and soles of feet. This cationic protein has also been shown to promote keratinocyte migration by activation of the epidermal growth factor receptor (EGFR). [provided by RefSeq, Dec 2015]
FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.02073437).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPINK9NM_001040433.2 linkc.14C>G p.Ala5Gly missense_variant Exon 1 of 4 ENST00000377906.2 NP_001035523.1 Q5DT21
SPINK9XM_017009709.2 linkc.119-795C>G intron_variant Intron 1 of 3 XP_016865198.1 D6RJC5
FBXO38-DTNR_105057.1 linkn.497-27462G>C intron_variant Intron 2 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPINK9ENST00000377906.2 linkc.14C>G p.Ala5Gly missense_variant Exon 1 of 4 1 NM_001040433.2 ENSP00000367139.1 Q5DT21

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
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:
0.000771
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000717
AC:
18
AN:
251144
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000979
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461340
Hom.:
1
Cov.:
30
AF XY:
0.0000316
AC XY:
23
AN XY:
727000
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00118
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000773
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.14C>G (p.A5G) alteration is located in exon 1 (coding exon 1) of the SPINK9 gene. This alteration results from a C to G substitution at nucleotide position 14, causing the alanine (A) at amino acid position 5 to be replaced by a glycine (G). 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
0.096
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
13
DANN
Benign
0.91
DEOGEN2
Benign
0.0023
T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.43
T
M_CAP
Benign
0.0029
T
MetaRNN
Benign
0.021
T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.32
T
PROVEAN
Benign
0.84
N
REVEL
Benign
0.041
Sift
Benign
0.42
T
Sift4G
Benign
0.42
T
Polyphen
0.73
P
Vest4
0.34
MVP
0.24
MPC
0.075
ClinPred
0.063
T
GERP RS
1.5
Varity_R
0.061
gMVP
0.30

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: rs201824427; hg19: chr5-147715190; API