NM_021115.5:c.581C>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021115.5(SEZ6L):​c.581C>G​(p.Pro194Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27163357).

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

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	NP_066938.2
	SEZ6L	NM_001184773.2		c.581C>G	p.Pro194Arg	missense	Exon 2 of 17	NP_001171702.1
	SEZ6L	NM_001184774.2		c.581C>G	p.Pro194Arg	missense	Exon 2 of 16	NP_001171703.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.097
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
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.043
MPC		0.48
ClinPred		0.70	D
GERP RS		3.5
Varity_R		0.080
gMVP		0.34
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2081181671; hg19: chr22-26688858;