rs12941884

Positions:

• chr17-28957425-A-G

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.2417T>C​(p.Met806Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,832 control chromosomes in the GnomAD database, including 17,228 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2045 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15183 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18

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=0.0040315986).
• BP6: Variant 17-28957425-A-G is Benign according to our data. Variant chr17-28957425-A-G is described in ClinVar as [Benign]. Clinvar id is 1239461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEZ6	NM_178860.5	c.2417T>C	p.Met806Thr	missense_variant	12/17	ENST00000317338.17	NP_849191.3
LOC105371716	XR_001752822.2	n.1807+4017A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17	c.2417T>C	p.Met806Thr	missense_variant	12/17	1	NM_178860.5	ENSP00000312942	A2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23727 AN: 152048 Hom.: 2041 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.153 AC: 38239 AN: 249192 Hom.: 3237 AF XY: 0.156 AC XY: 21047 AN XY: 135192

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.264

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.138 AC: 202001 AN: 1461666 Hom.: 15183 Cov.: 33 AF XY: 0.142 AC XY: 102995 AN XY: 727120

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0970

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.156 AC: 23753 AN: 152166 Hom.: 2045 Cov.: 32 AF XY: 0.157 AC XY: 11668 AN XY: 74386

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.147

Alfa AF: 0.133 Hom.: 3614

Bravo AF: 0.159

TwinsUK AF: 0.128 AC: 476

ALSPAC AF: 0.124 AC: 476

ESP6500AA AF: 0.198 AC: 773

ESP6500EA AF: 0.124 AC: 1033

ExAC AF: 0.155 AC: 18769

Asia WGS AF: 0.195 AC: 682 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.119

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	GeneDx	Feb 02, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.0030	.;T;T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.087	T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.61	N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.3	N;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;.;.;.;T
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.019
MPC		0.31
ClinPred		0.0016	T
GERP RS		3.6
Varity_R		0.084
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12941884; hg19: chr17-27284443; COSMIC: COSV57979972; COSMIC: COSV57979972;