22-26299111-G-T

Variant names:

• chr22-26299111-G-T
• rs663048
• NM_021115.5:c.1290G>T

Variant summary

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

The NM_021115.5(SEZ6L):​c.1290G>T​(p.Met430Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,601,428 control chromosomes in the GnomAD database, including 44,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.24 (4991 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39212 hom.)
• Consequence: SEZ6L NM_021115.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256
• Publications: 26 publications found

Genes affected

SEZ6L (HGNC:10763): (seizure related 6 homolog like) Predicted to act upstream of or within adult locomotory behavior; nervous system development; and regulation of protein kinase C signaling. Predicted to be located in endoplasmic reticulum and neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067515373).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021115.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6L	NM_021115.5	MANE Select	c.1290G>T	p.Met430Ile	missense	Exon 5 of 17	NP_066938.2
	SEZ6L	NM_001184773.2		c.1290G>T	p.Met430Ile	missense	Exon 5 of 17	NP_001171702.1
	SEZ6L	NM_001184774.2		c.1290G>T	p.Met430Ile	missense	Exon 5 of 16	NP_001171703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6L	ENST00000248933.11	TSL:1 MANE Select	c.1290G>T	p.Met430Ile	missense	Exon 5 of 17	ENSP00000248933.6
	SEZ6L	ENST00000404234.7	TSL:1	c.1290G>T	p.Met430Ile	missense	Exon 5 of 17	ENSP00000384772.3
	SEZ6L	ENST00000629590.2	TSL:1	c.1290G>T	p.Met430Ile	missense	Exon 5 of 16	ENSP00000485720.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37027 AN: 151970 Hom.: 4988 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.193 AC: 45983 AN: 238192 AF XY: 0.191

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.0670

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.226 AC: 328271 AN: 1449340 Hom.: 39212 Cov.: 32 AF XY: 0.223 AC XY: 160616 AN XY: 720586

African (AFR) AF: 0.330 AC: 10850 AN: 32838

American (AMR) AF: 0.115 AC: 4947 AN: 43094

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5117 AN: 25826

East Asian (EAS) AF: 0.0631 AC: 2439 AN: 38648

South Asian (SAS) AF: 0.0953 AC: 8026 AN: 84218

European-Finnish (FIN) AF: 0.227 AC: 12087 AN: 53156

Middle Eastern (MID) AF: 0.196 AC: 1117 AN: 5712

European-Non Finnish (NFE) AF: 0.245 AC: 270679 AN: 1106002

Other (OTH) AF: 0.217 AC: 13009 AN: 59846

GnomAD4 genome AF: 0.244 AC: 37052 AN: 152088 Hom.: 4991 Cov.: 32 AF XY: 0.240 AC XY: 17849 AN XY: 74348

African (AFR) AF: 0.322 AC: 13341 AN: 41486

American (AMR) AF: 0.173 AC: 2639 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 699 AN: 3472

East Asian (EAS) AF: 0.0627 AC: 324 AN: 5168

South Asian (SAS) AF: 0.0834 AC: 402 AN: 4820

European-Finnish (FIN) AF: 0.229 AC: 2426 AN: 10582

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16330 AN: 67952

Other (OTH) AF: 0.212 AC: 447 AN: 2106

Alfa AF: 0.236 Hom.: 17040

Bravo AF: 0.246

TwinsUK AF: 0.240 AC: 891

ALSPAC AF: 0.234 AC: 901

ESP6500AA AF: 0.315 AC: 1387

ESP6500EA AF: 0.233 AC: 2002

ExAC AF: 0.196 AC: 23795

Asia WGS AF: 0.101 AC: 352 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.6
DANN	Benign	0.88
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.080	N
PhyloP100		0.26
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.029
Sift	Benign	0.42	T
Sift4G	Benign	0.47	T
Polyphen		0.0070	B
Vest4		0.075
MutPred		0.24		Loss of catalytic residue at M430 (P = 0.0286)
MPC		0.12
ClinPred		0.000019	T
GERP RS		0.15
Varity_R		0.069
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs663048; hg19: chr22-26695077; COSMIC: COSV50662129;