NM_178860.5:c.1636A>G

Variant names:

• chr17-28959833-T-C
• rs1976165
• NM_178860.5:c.1636A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178860.5(SEZ6):​c.1636A>G​(p.Thr546Ala) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,613,136 control chromosomes in the GnomAD database, including 61,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8366 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53183 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86
• Publications: 33 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002216816).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

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.1636A>G	p.Thr546Ala	missense	Exon 8 of 17	NP_849191.3	Q53EL9-1
	SEZ6	NM_001098635.2		c.1636A>G	p.Thr546Ala	missense	Exon 8 of 17	NP_001092105.1	Q53EL9-3
	SEZ6	NM_001290202.2		c.1261A>G	p.Thr421Ala	missense	Exon 8 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.1636A>G	p.Thr546Ala	missense	Exon 8 of 17	ENSP00000312942.11	Q53EL9-1
	SEZ6	ENST00000540632.6	TSL:1	c.1414A>G	p.Thr472Ala	missense	Exon 7 of 16	ENSP00000437650.2	H0YF95
	SEZ6	ENST00000360295.13	TSL:5	c.1636A>G	p.Thr546Ala	missense	Exon 8 of 17	ENSP00000353440.9	Q53EL9-3

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48194 AN: 151970 Hom.: 8360 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.327

GnomAD2 exomes AF: 0.283 AC: 70036 AN: 247794 AF XY: 0.284

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.265 AC: 387339 AN: 1461046 Hom.: 53183 Cov.: 36 AF XY: 0.267 AC XY: 194316 AN XY: 726752

African (AFR) AF: 0.469 AC: 15699 AN: 33472

American (AMR) AF: 0.268 AC: 11939 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 7041 AN: 26106

East Asian (EAS) AF: 0.248 AC: 9842 AN: 39694

South Asian (SAS) AF: 0.363 AC: 31262 AN: 86172

European-Finnish (FIN) AF: 0.264 AC: 14062 AN: 53362

Middle Eastern (MID) AF: 0.311 AC: 1789 AN: 5748

European-Non Finnish (NFE) AF: 0.250 AC: 278333 AN: 1111534

Other (OTH) AF: 0.288 AC: 17372 AN: 60356

GnomAD4 genome AF: 0.317 AC: 48231 AN: 152090 Hom.: 8366 Cov.: 32 AF XY: 0.317 AC XY: 23575 AN XY: 74362

African (AFR) AF: 0.460 AC: 19053 AN: 41436

American (AMR) AF: 0.300 AC: 4589 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3466

East Asian (EAS) AF: 0.239 AC: 1237 AN: 5174

South Asian (SAS) AF: 0.364 AC: 1754 AN: 4820

European-Finnish (FIN) AF: 0.266 AC: 2814 AN: 10588

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16837 AN: 67994

Other (OTH) AF: 0.324 AC: 685 AN: 2112

Alfa AF: 0.274 Hom.: 19504

Bravo AF: 0.326

TwinsUK AF: 0.248 AC: 920

ALSPAC AF: 0.253 AC: 975

ESP6500AA AF: 0.429 AC: 1790

ESP6500EA AF: 0.255 AC: 2162

ExAC AF: 0.287 AC: 34741

Asia WGS AF: 0.339 AC: 1182 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.262

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.73	N
PhyloP100		5.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.079
Sift	Benign	0.31	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.26
ClinPred		0.0076	T
GERP RS		5.1
Varity_R		0.067
gMVP		0.26
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1976165; hg19: chr17-27286851; COSMIC: COSV100252716; COSMIC: COSV100252716;