17-28959404-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_178860.5(SEZ6):c.1840G>A(p.Gly614Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,950 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (53 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.43

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006298989).
• BP6: Variant 17-28959404-C-T is Benign according to our data. Variant chr17-28959404-C-T is described in ClinVar as [Benign]. Clinvar id is 790331.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-28959404-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0023 (350/152288) while in subpopulation SAS AF= 0.0184 (89/4828). AF 95% confidence interval is 0.0153. There are 1 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6	NM_178860.5	c.1840G>A	p.Gly614Ser	missense_variant	9/17	ENST00000317338.17
LOC105371716	XR_001752822.2	n.1807+5996C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEZ6	ENST00000317338.17	c.1840G>A	p.Gly614Ser	missense_variant	9/17	1	NM_178860.5	A2

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00474 AC: 1181 AN: 249080 Hom.: 17 AF XY: 0.00572 AC XY: 773 AN XY: 135130

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00776

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.00386

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00301 AC: 4406 AN: 1461662 Hom.: 53 Cov.: 32 AF XY: 0.00360 AC XY: 2616 AN XY: 727120

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00899

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.00424

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74466

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00161

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.00259 AC: 22

ExAC AF: 0.00518 AC: 627

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.70
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T;T;T;T
MetaRNN	Benign	0.0063	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.80	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.40	N;.;.;.;N
REVEL	Benign	0.030
Sift	Benign	0.99	T;.;.;.;T
Sift4G	Benign	0.89	T;T;T;T;T
Polyphen		0.14	B;.;B;.;.
Vest4		0.24
MVP		0.35
MPC		0.30
ClinPred		0.0081	T
GERP RS		4.3
Varity_R		0.033
gMVP		0.47

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: rs201206867; hg19: chr17-27286422; COSMIC: COSV57977945; COSMIC: COSV57977945;