Variant chr17-28956196-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000317338.17(SEZ6):c.2915T>C(p.Ile972Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 768,248 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00021 ( 4 hom. )

Consequence

SEZ6
ENST00000317338.17 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04814729).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6	NM_178860.5 linkuse as main transcript	c.2915T>C	p.Ile972Thr	missense_variant	16/17	ENST00000317338.17	NP_849191.3
LOC105371716	XR_001752822.2 linkuse as main transcript	n.1807+2788A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17 linkuse as main transcript	c.2915T>C	p.Ile972Thr	missense_variant	16/17	1	NM_178860.5	ENSP00000312942	A2	Q53EL9-1

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

87360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000850

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

240760

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

130926

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.000677

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000774

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

142

AN:

680854

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

110

AN XY:

354948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000619

Gnomad4 AMR exome

AF:

0.000768

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000858

Gnomad4 OTH exome

AF:

0.0000759

GnomAD4 genome

AF:

0.000126

AC:

AN:

87394

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

40306

show subpopulations

Gnomad4 AFR

AF:

0.0000458

Gnomad4 AMR

AF:

0.000171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00212

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000850

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000231

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

Jan 26, 2023

The c.2915T>C (p.I972T) alteration is located in exon 16 (coding exon 16) of the SEZ6 gene. This alteration results from a T to C substitution at nucleotide position 2915, causing the isoleucine (I) at amino acid position 972 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

0.099

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

.;T;T;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.048

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;N;.;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.3

N;.;.;.;.

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;.;.;.;.

Sift4G

Benign

0.075

T;T;T;T;T

Polyphen

0.034

B;.;B;.;.

Vest4

0.25

MutPred

0.60

Loss of sheet (P = 0.0025);.;Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);.;

MVP

0.31

MPC

0.34

ClinPred

0.064

GERP RS

5.5

Varity_R

0.14

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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