Genetic Variant SEZ6L:p.Ala3Val (chr22-26169677-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021115.5(SEZ6L):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000611 in 1,309,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

SEZ6L
NM_021115.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0270

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050223142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEZ6L	NM_021115.5 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 17	ENST00000248933.11	NP_066938.2	Q9BYH1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEZ6L	ENST00000248933.11 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 17	1	NM_021115.5	ENSP00000248933.6		Q9BYH1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1157486

Hom.:

Cov.:

AF XY:

0.00000178

AC XY:

AN XY:

562398

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

AC:

AN:

23636

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

13200

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

16854

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

27000

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

43242

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

26490

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

957340

Gnomad4 Remaining exome

AF:

0.0000215

AC:

AN:

46540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000966

AC:

0.0000966044

AN:

0.0000966044

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8C>T (p.A3V) alteration is located in exon 1 (coding exon 1) of the SEZ6L gene. This alteration results from a C to T substitution at nucleotide position 8, causing the alanine (A) at amino acid position 3 to be replaced by a valine (V). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0077

.;T;.;.;T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.63

T;T;T;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.050

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;N;N;N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.54

N;N;N;.;N;N

REVEL

Benign

0.079

Sift

Benign

0.83

T;T;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0070, 0.022

.;B;B;.;B;B

Vest4

0.087

MutPred

0.19

Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);

MVP

0.043

MPC

0.099

ClinPred

0.086

GERP RS

0.87

Varity_R

0.030

gMVP

0.26

Mutation Taster

=93/7

polymorphism

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