chr17-28957525-C-T

Variant names:

• chr17-28957525-C-T
• rs914000193
• NM_178860.5:c.2317G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178860.5(SEZ6):​c.2317G>A​(p.Asp773Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,612,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82
• Publications: 0 publications found

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]

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]

LOC105371716 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178860.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6	NM_178860.5	MANE Select	c.2317G>A	p.Asp773Asn	missense	Exon 12 of 17	NP_849191.3	Q53EL9-1
	SEZ6	NM_001098635.2		c.2317G>A	p.Asp773Asn	missense	Exon 12 of 17	NP_001092105.1	Q53EL9-3
	SEZ6	NM_001290202.2		c.1942G>A	p.Asp648Asn	missense	Exon 12 of 17	NP_001277131.1	Q53EL9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6	ENST00000317338.17	TSL:1 MANE Select	c.2317G>A	p.Asp773Asn	missense	Exon 12 of 17	ENSP00000312942.11	Q53EL9-1
	SEZ6	ENST00000540632.6	TSL:1	c.2095G>A	p.Asp699Asn	missense	Exon 11 of 16	ENSP00000437650.2	H0YF95
	SEZ6	ENST00000360295.13	TSL:5	c.2317G>A	p.Asp773Asn	missense	Exon 12 of 17	ENSP00000353440.9	Q53EL9-3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151428 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247030 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461380 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 726958

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111698

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151428 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73902

African (AFR) AF: 0.0000243 AC: 1 AN: 41128

American (AMR) AF: 0.00 AC: 0 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.56		Loss of disorder (P = 0.1205)
MVP		0.80
MPC		0.93
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.55
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs914000193; hg19: chr17-27284543; COSMIC: COSV57977788; COSMIC: COSV57977788;