2-201330770-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001127391.3(FLACC1):c.588G>C(p.Leu196Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,872 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 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
FLACC1
NM_001127391.3 missense
NM_001127391.3 missense
Scores
8
10
Clinical Significance
Conservation
PhyloP100: 1.85
Genes affected
FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]
CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.24761379).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLACC1 | NM_001127391.3 | c.588G>C | p.Leu196Phe | missense_variant | 8/15 | ENST00000392257.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLACC1 | ENST00000392257.8 | c.588G>C | p.Leu196Phe | missense_variant | 8/15 | 1 | NM_001127391.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152132Hom.: 0 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250960Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135624
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GnomAD4 exome AF: 0.000148 AC: 217AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117AN XY: 727154
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74330
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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 submitter | clinical testing | Ambry Genetics | Jan 06, 2023 | The c.588G>C (p.L196F) alteration is located in exon 8 (coding exon 7) of the ALS2CR12 gene. This alteration results from a G to C substitution at nucleotide position 588, causing the leucine (L) at amino acid position 196 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;.
Polyphen
D;D;.;.;.
Vest4
MutPred
Gain of methylation at K197 (P = 0.0294);Gain of methylation at K197 (P = 0.0294);Gain of methylation at K197 (P = 0.0294);Gain of methylation at K197 (P = 0.0294);.;
MVP
MPC
0.27
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at