chr17-28956230-G-A

Position:

• chr17-28956230-G-A

Variant summary

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

The ENST00000317338.17(SEZ6):​c.2881C>T​(p.Arg961Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 525,648 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R961H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SEZ6 ENST00000317338.17 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056946576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6	NM_178860.5	c.2881C>T	p.Arg961Cys	missense_variant	16/17	ENST00000317338.17	NP_849191.3
LOC105371716	XR_001752822.2	n.1807+2822G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17	c.2881C>T	p.Arg961Cys	missense_variant	16/17	1	NM_178860.5	ENSP00000312942	A2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 30 AN: 138300 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000158

Gnomad OTH AF: 0.000513

GnomAD3 exomes AF: 0.0000689 AC: 15 AN: 217560 Hom.: 0 AF XY: 0.0000755 AC XY: 9 AN XY: 119258

Gnomad AFR exome AF: 0.000828

Gnomad AMR exome AF: 0.0000313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000315

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 70 AN: 387204 Hom.: 0 Cov.: 0 AF XY: 0.000188 AC XY: 41 AN XY: 218012

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.0000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000153

Gnomad4 FIN exome AF: 0.0000340

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.000179

GnomAD4 genome AF: 0.000217 AC: 30 AN: 138444 Hom.: 0 Cov.: 32 AF XY: 0.000194 AC XY: 13 AN XY: 66970

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000158

Gnomad4 OTH AF: 0.000507

Alfa AF: 0.0000653 Hom.: 0

ExAC AF: 0.0000252 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.2881C>T (p.R961C) alteration is located in exon 16 (coding exon 16) of the SEZ6 gene. This alteration results from a C to T substitution at nucleotide position 2881, causing the arginine (R) at amino acid position 961 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	.;T;T;.;T
Eigen	Benign	-0.0021
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.057	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.17	N;.;.;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.014	D;.;.;.;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.99	D;.;P;.;.
Vest4		0.37
MVP		0.37
MPC		0.61
ClinPred		0.044	T
GERP RS		3.4
Varity_R		0.084
gMVP		0.58

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: rs199955003; hg19: chr17-27283248;