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GeneBe

16-29872437-C-T

Variant summary

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

The NM_001243332.2(SEZ6L2):c.2617G>A(p.Gly873Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,178 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 (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SEZ6L2
NM_001243332.2 missense

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58
Variant links:
Genes affected
SEZ6L2 (HGNC:30844): (seizure related 6 homolog like 2) This gene encodes a seizure-related protein that is localized on the cell surface. The gene is located in a region of chromosome 16p11.2 that is thought to contain candidate genes for autism spectrum disorders (ASD), though there is no evidence directly implicating this gene in ASD. Increased expression of this gene has been found in lung cancers, and the protein is therefore considered to be a novel prognostic marker for lung cancer. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

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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=0.020589024).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEZ6L2NM_001243332.2 linkuse as main transcriptc.2617G>A p.Gly873Ser missense_variant 16/18 ENST00000617533.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEZ6L2ENST00000617533.5 linkuse as main transcriptc.2617G>A p.Gly873Ser missense_variant 16/181 NM_001243332.2 P1

Frequencies

GnomAD3 genomes
AF:
0.000480
AC:
73
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00174
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251410
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00166
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.0000410
AC:
60
AN:
1461872
Hom.:
0
Cov.:
32
AF XY:
0.0000330
AC XY:
24
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00131
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000486
AC:
74
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000457
AC XY:
34
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00176
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000131
Hom.:
0
Bravo
AF:
0.000525
ESP6500AA
AF:
0.00205
AC:
9
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000148
AC:
18

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 GeneticsJan 27, 2022The c.2578G>A (p.G860S) alteration is located in exon 15 (coding exon 15) of the SEZ6L2 gene. This alteration results from a G to A substitution at nucleotide position 2578, causing the glycine (G) at amino acid position 860 to be replaced by a serine (S). 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
0.15
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.43
Cadd
Benign
22
Dann
Uncertain
1.0
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.079
FATHMM_MKL
Benign
0.48
N
LIST_S2
Uncertain
0.86
D;D;D;D;D
M_CAP
Benign
0.0091
T
MetaRNN
Benign
0.021
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.98
D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
1.1
N;N;N;N;.
REVEL
Benign
0.11
Sift
Uncertain
0.021
D;D;D;D;.
Sift4G
Uncertain
0.0070
D;D;D;D;D
Polyphen
0.90, 0.71
.;P;P;.;.
Vest4
0.25
MVP
0.35
MPC
0.36
ClinPred
0.035
T
GERP RS
4.4
Varity_R
0.045
gMVP
0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149666804; hg19: chr16-29883758; API