17-28956734-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_178860.5(SEZ6):c.2716A>G(p.Ser906Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000851 in 1,563,686 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.524

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]

LOC105371716 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061712563).
• BP6: Variant 17-28956734-T-C is Benign according to our data. Variant chr17-28956734-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2243731.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6	NM_178860.5	c.2716A>G	p.Ser906Gly	missense_variant	14/17	ENST00000317338.17
LOC105371716	XR_001752822.2	n.1807+3326T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEZ6	ENST00000317338.17	c.2716A>G	p.Ser906Gly	missense_variant	14/17	1	NM_178860.5	A2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.00143

GnomAD3 exomes AF: 0.000144 AC: 25 AN: 174198 Hom.: 0 AF XY: 0.0000865 AC XY: 8 AN XY: 92504

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.000307

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: 0.0000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 70 AN: 1411332 Hom.: 0 Cov.: 32 AF XY: 0.0000373 AC XY: 26 AN XY: 697268

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000352

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: 0.00000276

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74490

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.000392

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: 0.00142

Alfa AF: 0.0000811 Hom.: 0

Bravo AF: 0.000544

ESP6500AA AF: 0.00125 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000111 AC: 13

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.66
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.52	N;.;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.61	N;.;.
REVEL	Benign	0.033
Sift	Benign	0.67	T;.;.
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.11
MVP		0.14
MPC		0.25
ClinPred		0.0012	T
GERP RS		1.3
Varity_R		0.056
gMVP		0.36

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

Other links and lift over

dbSNP: rs148336598; hg19: chr17-27283752;