Variant chr17-28956459-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.2740G>A(p.Ala914Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,401,656 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: not found (cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

SEZ6
NM_178860.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.222

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:

SEZ6 (HGNC:):

SEZ6 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=0.066533774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6	NM_178860.5 linkuse as main transcript	c.2740G>A	p.Ala914Thr	missense_variant	15/17	ENST00000317338.17	NP_849191.3	Q53EL9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17 linkuse as main transcript	c.2740G>A	p.Ala914Thr	missense_variant	15/17	1	NM_178860.5	ENSP00000312942.11		Q53EL9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000313

AC:

AN:

159886

Hom.:

AF XY:

0.0000236

AC XY:

AN XY:

84620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000444

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000499

AC:

AN:

1401656

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000194

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

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

May 28, 2024

The c.2740G>A (p.A914T) 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 2740, causing the alanine (A) at amino acid position 914 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

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.0098

.;T;T;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.74

T;T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.067

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;.;L;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.98

N;.;.;.;.

REVEL

Benign

0.035

Sift

Benign

0.59

T;.;.;.;.

Sift4G

Benign

0.69

T;T;T;T;T

Polyphen

0.42

B;.;B;.;.

Vest4

0.089

MutPred

0.28

Gain of glycosylation at A914 (P = 0.0097);.;Gain of glycosylation at A914 (P = 0.0097);Gain of glycosylation at A914 (P = 0.0097);.;

MVP

0.35

MPC

0.26

ClinPred

0.066

GERP RS

3.5

Varity_R

0.092

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