3-140421148-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000458420.7(CLSTN2):c.661C>A(p.Leu221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
CLSTN2
ENST00000458420.7 missense
ENST00000458420.7 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 0.829
Genes affected
CLSTN2 (HGNC:17448): (calsyntenin 2) Predicted to enable calcium ion binding activity. Predicted to be involved in positive regulation of synapse assembly and positive regulation of synaptic transmission. Predicted to be located in postsynaptic density. Predicted to be active in cell surface; glutamatergic synapse; and postsynaptic membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]
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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 |
---|---|---|---|---|---|---|---|---|
CLSTN2 | NM_022131.3 | c.661C>A | p.Leu221Met | missense_variant | 5/17 | ENST00000458420.7 | NP_071414.2 | |
CLSTN2 | XM_017007022.3 | c.586C>A | p.Leu196Met | missense_variant | 5/17 | XP_016862511.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLSTN2 | ENST00000458420.7 | c.661C>A | p.Leu221Met | missense_variant | 5/17 | 1 | NM_022131.3 | ENSP00000402460 | P1 | |
CLSTN2 | ENST00000511524.1 | n.849C>A | non_coding_transcript_exon_variant | 5/11 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000677 AC: 17AN: 250982Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135606
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461720Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727156
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74380
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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 | Feb 13, 2024 | The c.661C>A (p.L221M) alteration is located in exon 5 (coding exon 5) of the CLSTN2 gene. This alteration results from a C to A substitution at nucleotide position 661, causing the leucine (L) at amino acid position 221 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of methylation at K225 (P = 0.0474);
MVP
MPC
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