NM_021115.5:c.581C>G

Variant names:

• chr22-26292892-C-G
• rs2081181671
• NM_021115.5:c.581C>G
• SEZ6L p.Pro194Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_021115.5(SEZ6L):c.581C>G (p.Pro194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEZ6L NM_021115.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18
• Publications: 0 publications found

Genes affected

SEZ6L (HGNC:10763): (seizure related 6 homolog like) Predicted to be involved in synapse maturation. Predicted to act upstream of or within activation of protein kinase C activity; adult locomotory behavior; and cerebellar Purkinje cell layer development. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in several cellular components, including glutamatergic synapse; neuronal cell body; and postsynaptic membrane. [provided by Alliance of Genome Resources, Jul 2025]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SEZ6L NM_021115.5	MANE Select	c.581C>G p.Pro194Arg	missense	Exon 2 of 17	Prot: NP_066938.2
	SEZ6L NM_001184773.2		c.581C>G p.Pro194Arg	missense	Exon 2 of 17	Prot: NP_001171702.1 UniProt:
	SEZ6L NM_001184774.2		c.581C>G p.Pro194Arg	missense	Exon 2 of 16	Prot: NP_001171703.1 UniProt:

SEZ6L NM_021115.5

MANE Select

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 17

missense

Prot: NP_066938.2

SEZ6L NM_001184773.2

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 17

missense

Prot: NP_001171702.1UniProt: Q9BYH1-6

SEZ6L NM_001184774.2

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 16

missense

Prot: NP_001171703.1UniProt: Q9BYH1-7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SEZ6L ENST00000248933.11	TSL:1MANE Select	c.581C>G p.Pro194Arg	missense	Exon 2 of 17	Prot: ENSP00000248933.6 UniProt:
	SEZ6L ENST00000404234.7	TSL:1	c.581C>G p.Pro194Arg	missense	Exon 2 of 17	Prot: ENSP00000384772.3 UniProt:
	SEZ6L ENST00000629590.2	TSL:1	c.581C>G p.Pro194Arg	missense	Exon 2 of 16	Prot: ENSP00000485720.1 UniProt:

SEZ6L ENST00000248933.11

TSL:1MANE Select

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 17

missense

Prot: ENSP00000248933.6UniProt: Q9BYH1-1

SEZ6L ENST00000404234.7

TSL:1

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 17

missense

Prot: ENSP00000384772.3UniProt: Q9BYH1-6

SEZ6L ENST00000629590.2

TSL:1

HGVSc / HGVSpc.581C>Gp.Pro194Arg

Exon rankExon 2 of 16

missense

Prot: ENSP00000485720.1UniProt: Q9BYH1-7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.018
GPN-Star LLR	N/A	-7.2
GPN-Star score	N/A	7.2
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	83/17	polymorphism
MutationAssessor	Benign	0.81	L
PhyloP100	Uncertain	4.2
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.080
VESM-3B	Benign	-4.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2081181671;

hg19: chr22-26688858;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar