Variant 22-26292655-C-G 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.344C>G(p.Pro115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,613,300 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 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SEZ6L
NM_021115.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

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=0.012132168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6L	NM_021115.5 linkuse as main transcript	c.344C>G	p.Pro115Arg	missense_variant	2/17	ENST00000248933.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEZ6L	ENST00000248933.11 linkuse as main transcript	c.344C>G	p.Pro115Arg	missense_variant	2/17	1	NM_021115.5	P4	Q9BYH1-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000112

AC:

AN:

249110

Hom.:

AF XY:

0.0000668

AC XY:

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.00150

Gnomad AMR exome

AF:

0.0000870

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461018

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000466

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00168

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:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000638

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

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, 2023

The c.344C>G (p.P115R) 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 344, causing the proline (P) at amino acid position 115 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

0.080

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.92

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.012

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

0.28

PROVEAN

Benign

-0.42

N;N;N;.;N;N

REVEL

Benign

0.016

Sift

Benign

0.065

T;T;T;.;T;T

Sift4G

Benign

0.12

T;T;T;T;T;T

Polyphen

0.089, 0.43, 0.037, 0.14

.;B;B;.;B;B

Vest4

0.19

MVP

0.13

MPC

0.17

ClinPred

0.0053

GERP RS

2.6

Varity_R

0.031

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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