17-28957176-T-C

Position:

• chr17-28957176-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178860.5(SEZ6):​c.2561A>G​(p.Gln854Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,613,996 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (67 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (69 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.273

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013213754).
• BP6: Variant 17-28957176-T-C is Benign according to our data. Variant chr17-28957176-T-C is described in ClinVar as [Benign]. Clinvar id is 785563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6	NM_178860.5	c.2561A>G	p.Gln854Arg	missense_variant	13/17	ENST00000317338.17	NP_849191.3
LOC105371716	XR_001752822.2	n.1807+3768T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17	c.2561A>G	p.Gln854Arg	missense_variant	13/17	1	NM_178860.5	ENSP00000312942	A2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2560 AN: 152192 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00426 AC: 1061 AN: 249184 Hom.: 24 AF XY: 0.00305 AC XY: 413 AN XY: 135198

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00158 AC: 2313 AN: 1461686 Hom.: 69 Cov.: 32 AF XY: 0.00139 AC XY: 1014 AN XY: 727128

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.0168 AC: 2565 AN: 152310 Hom.: 67 Cov.: 32 AF XY: 0.0158 AC XY: 1173 AN XY: 74466

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00320 Hom.: 20

Bravo AF: 0.0192

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0495 AC: 205

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00547 AC: 662

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.78
DANN	Benign	0.69
DEOGEN2	Benign	0.0029	.;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.040	T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.8	N;.;.;.;N
REVEL	Benign	0.058
Sift	Benign	1.0	T;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.12
MVP		0.26
MPC		0.29
ClinPred		0.0014	T
GERP RS		2.6
Varity_R		0.036
gMVP		0.39

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

Other links and lift over

dbSNP: rs61737974; hg19: chr17-27284194;