Variant 17-28956432-C-T 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_178860.5(SEZ6):c.2767G>A(p.Ala923Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000212 in 1,562,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SEZ6
NM_178860.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

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 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=0.046560585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6	NM_178860.5 linkuse as main transcript	c.2767G>A	p.Ala923Thr	missense_variant	15/17	ENST00000317338.17
LOC105371716	XR_001752822.2 linkuse as main transcript	n.1807+3024C>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.2767G>A	p.Ala923Thr	missense_variant	15/17	1	NM_178860.5	A2	Q53EL9-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

171016

Hom.:

AF XY:

0.0000992

AC XY:

AN XY:

90724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000302

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000430

GnomAD4 exome

AF:

0.000193

AC:

272

AN:

1410346

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

144

AN XY:

696658

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000791

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000627

Gnomad4 NFE exome

AF:

0.000204

Gnomad4 OTH exome

AF:

0.000308

GnomAD4 genome

AF:

0.000394

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000238

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

Dec 13, 2022

The c.2767G>A (p.A923T) alteration is located in exon 15 (coding exon 15) of the SEZ6 gene. This alteration results from a G to A substitution at nucleotide position 2767, causing the alanine (A) at amino acid position 923 to be replaced by a threonine (T). 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

-0.42

BayesDel_noAF

Benign

-0.38

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D;D;D;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.047

T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.3

M;.;M;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

N;.;.;.;.

REVEL

Benign

0.067

Sift

Uncertain

0.0050

D;.;.;.;.

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.45

B;.;B;.;.

Vest4

0.20

MVP

0.50

MPC

0.27

ClinPred

0.18

GERP RS

5.6

Varity_R

0.17

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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