17-28957966-G-T

Variant summary

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

The NM_178860.5(SEZ6):c.2283C>A(p.Asp761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SEZ6
NM_178860.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

SEZ6 (HGNC:15955): (seizure related 6 homolog) The protein encoded by this gene is thought to contain five cysteine-rich motifs that are similar to sushi domains, as well as two domains similar to the amino terminal half of the CUB (for complement C1r/C1s, Uegf, Bmp1) domain. Mutations in this gene have been associated with febrile seizures. [provided by RefSeq, Jul 2016]

SEZ6 links:

LOC105371716 (HGNC:):

LOC105371716 links:

PIPOX (HGNC:17804): (pipecolic acid and sarcosine oxidase) Enables L-pipecolate oxidase activity and sarcosine oxidase activity. Involved in L-lysine catabolic process to acetyl-CoA via L-pipecolate. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

PIPOX links:

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=0.19600794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6	NM_178860.5 linkuse as main transcript	c.2283C>A	p.Asp761Glu	missense_variant	11/17	ENST00000317338.17
LOC105371716	XR_001752822.2 linkuse as main transcript	n.1807+4558G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEZ6	ENST00000317338.17 linkuse as main transcript	c.2283C>A	p.Asp761Glu	missense_variant	11/17	1	NM_178860.5	A2	Q53EL9-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

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:

0.0000321

AC:

AN:

249046

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000138

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00137

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

Bravo

AF:

0.000132

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

Apr 13, 2023

The c.2283C>A (p.D761E) alteration is located in exon 11 (coding exon 11) of the SEZ6 gene. This alteration results from a C to A substitution at nucleotide position 2283, causing the aspartic acid (D) at amino acid position 761 to be replaced by a glutamic acid (E). 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

0.20

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Benign

0.13

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.27

N;.;N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

N;.;.;.;N

REVEL

Uncertain

0.30

Sift

Benign

0.22

T;.;.;.;T

Sift4G

Benign

0.27

T;T;T;T;T

Polyphen

0.99

D;.;D;.;.

Vest4

0.57

MutPred

0.33

Gain of disorder (P = 0.1677);.;Gain of disorder (P = 0.1677);Gain of disorder (P = 0.1677);Gain of disorder (P = 0.1677);

MVP

0.75

MPC

0.91

ClinPred

0.58

GERP RS

2.4

Varity_R

0.15

gMVP

0.33

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