22-26292898-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021115.5(SEZ6L):ā€‹c.587C>Gā€‹(p.Thr196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000099 ( 0 hom., cov: 32)
Exomes š‘“: 0.00013 ( 0 hom. )

Consequence

SEZ6L
NM_021115.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66
Variant links:
Genes affected
SEZ6L (HGNC:10763): (seizure related 6 homolog like) Predicted to act upstream of or within adult locomotory behavior; nervous system development; and regulation of protein kinase C signaling. Predicted to be located in endoplasmic reticulum and neuronal cell body. [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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.088831395).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEZ6LNM_021115.5 linkuse as main transcriptc.587C>G p.Thr196Arg missense_variant 2/17 ENST00000248933.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEZ6LENST00000248933.11 linkuse as main transcriptc.587C>G p.Thr196Arg missense_variant 2/171 NM_021115.5 P4Q9BYH1-1

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152192
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000761
AC:
19
AN:
249752
Hom.:
0
AF XY:
0.0000961
AC XY:
13
AN XY:
135338
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:
0.0000980
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000133
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000135
AC:
197
AN:
1461868
Hom.:
0
Cov.:
34
AF XY:
0.000146
AC XY:
106
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000164
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000254
Hom.:
0
Bravo
AF:
0.0000869
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
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 GeneticsFeb 27, 2024The c.587C>G (p.T196R) alteration is located in exon 2 (coding exon 2) of the SEZ6L gene. This alteration results from a C to G substitution at nucleotide position 587, causing the threonine (T) at amino acid position 196 to be replaced by an arginine (R). 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
0.11
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.011
.;T;.;.;T;.
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.80
T;T;T;T;T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.089
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.81
L;.;L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.69
N;N;N;.;N;N
REVEL
Benign
0.071
Sift
Uncertain
0.0060
D;D;D;.;D;D
Sift4G
Benign
0.57
T;T;T;T;T;T
Polyphen
0.87, 0.96, 0.93, 0.98
.;P;D;.;P;D
Vest4
0.28
MVP
0.082
MPC
0.21
ClinPred
0.049
T
GERP RS
3.5
Varity_R
0.089
gMVP
0.42

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: rs141695407; hg19: chr22-26688864; API