chr16-89828618-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032451.2(SPIRE2):ā€‹c.68C>Gā€‹(p.Ser23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,321,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000067 ( 0 hom., cov: 32)
Exomes š‘“: 8.5e-7 ( 0 hom. )

Consequence

SPIRE2
NM_032451.2 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
SPIRE2 (HGNC:30623): (spire type actin nucleation factor 2) Predicted to enable actin binding activity. Involved in establishment of meiotic spindle localization; formin-nucleated actin cable assembly; and positive regulation of double-strand break repair. Predicted to be located in cytoskeleton; cytosol; and plasma membrane. Predicted to be active in cell cortex and cytoplasmic vesicle membrane. Predicted to colocalize with cleavage furrow. [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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPIRE2NM_032451.2 linkuse as main transcriptc.68C>G p.Ser23Cys missense_variant 1/15 ENST00000378247.8 NP_115827.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPIRE2ENST00000378247.8 linkuse as main transcriptc.68C>G p.Ser23Cys missense_variant 1/151 NM_032451.2 ENSP00000367494 P1Q8WWL2-1
SPIRE2ENST00000393062.6 linkuse as main transcriptc.68C>G p.Ser23Cys missense_variant 1/131 ENSP00000376782 Q8WWL2-2
SPIRE2ENST00000563972.1 linkuse as main transcriptc.68C>G p.Ser23Cys missense_variant 1/31 ENSP00000457940
SPIRE2ENST00000564878.5 linkuse as main transcriptn.360+10080C>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000669
AC:
1
AN:
149520
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:
0.000195
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
GnomAD4 exome
AF:
8.53e-7
AC:
1
AN:
1172234
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
575986
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:
0.00
Gnomad4 OTH exome
AF:
0.0000222
GnomAD4 genome
AF:
0.00000668
AC:
1
AN:
149628
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
72960
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2021The c.68C>G (p.S23C) alteration is located in exon 1 (coding exon 1) of the SPIRE2 gene. This alteration results from a C to G substitution at nucleotide position 68, causing the serine (S) at amino acid position 23 to be replaced by a cysteine (C). 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
0.25
BayesDel_addAF
Benign
-0.014
T
BayesDel_noAF
Benign
-0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.050
.;T;.
Eigen
Uncertain
0.31
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.84
T;T;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Uncertain
0.57
D;D;D
MetaSVM
Benign
-0.73
T
MutationAssessor
Uncertain
2.4
M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-2.2
N;N;D
REVEL
Uncertain
0.30
Sift
Benign
0.049
D;D;D
Sift4G
Benign
0.081
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.55
MutPred
0.51
Gain of catalytic residue at L24 (P = 0.0103);Gain of catalytic residue at L24 (P = 0.0103);Gain of catalytic residue at L24 (P = 0.0103);
MVP
0.34
MPC
0.65
ClinPred
0.97
D
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.62
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89895026; API