Variant chr22-26292594-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021115.5(SEZ6L):c.283G>A(p.Asp95Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SEZ6L
NM_021115.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

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]

SEZ6L links:

Genome browser will be placed here

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=0.057681948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6L	NM_021115.5 linkuse as main transcript	c.283G>A	p.Asp95Asn	missense_variant	2/17	ENST00000248933.11	NP_066938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6L	ENST00000248933.11 linkuse as main transcript	c.283G>A	p.Asp95Asn	missense_variant	2/17	1	NM_021115.5	ENSP00000248933	P4	Q9BYH1-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249358

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

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 submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.283G>A (p.D95N) alteration is located in exon 2 (coding exon 2) of the SEZ6L gene. This alteration results from a G to A substitution at nucleotide position 283, causing the aspartic acid (D) at amino acid position 95 to be replaced by an asparagine (N). 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

0.070

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.0078

.;T;.;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.73

T;T;T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.058

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.24

N;N;N;.;N;N

REVEL

Benign

0.021

Sift

Benign

0.12

T;T;T;.;T;T

Sift4G

Benign

0.47

T;T;T;T;T;T

Polyphen

0.082, 0.13

.;B;B;.;B;B

Vest4

0.12

MutPred

0.11

Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);

MVP

0.068

MPC

0.098

ClinPred

0.030

GERP RS

1.3

Varity_R

0.067

gMVP

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over