22-26292634-G-A

Variant names:

• chr22-26292634-G-A
• rs764095767
• NM_021115.5:c.323G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021115.5(SEZ6L):​c.323G>A​(p.Arg108His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: SEZ6L NM_021115.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04539302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEZ6L	NM_021115.5	c.323G>A	p.Arg108His	missense_variant	Exon 2 of 17	ENST00000248933.11	NP_066938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEZ6L	ENST00000248933.11	c.323G>A	p.Arg108His	missense_variant	Exon 2 of 17	1	NM_021115.5	ENSP00000248933.6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000927 AC: 23 AN: 248084 AF XY: 0.0000894

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1460584 Hom.: 0 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726568

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33466

Gnomad4 AMR exome AF: 0.0000672 AC: 3 AN: 44638

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26108

Gnomad4 EAS exome AF: 0.00134 AC: 53 AN: 39646

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86062

Gnomad4 FIN exome AF: 0.0000189 AC: 1 AN: 52894

Gnomad4 NFE exome AF: 0.0000342 AC: 38 AN: 1111650

Gnomad4 Remaining exome AF: 0.0000663 AC: 4 AN: 60354

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74236

Gnomad4 AFR AF: 0.0000725 AC: 0.0000724778 AN: 0.0000724778

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000387 AC: 0.000387147 AN: 0.000387147

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000589 AC: 0.0000588512 AN: 0.0000588512

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000768 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323G>A (p.R108H) alteration is located in exon 2 (coding exon 2) of the SEZ6L gene. This alteration results from a G to A substitution at nucleotide position 323, causing the arginine (R) at amino acid position 108 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0027	.;T;.;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.045	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.050	N;N;N;.;N;N
REVEL	Benign	0.034
Sift	Benign	0.11	T;T;T;.;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.70, 0.98, 0.47, 0.80	.;P;D;.;P;P
Vest4		0.11
MVP		0.13
MPC		0.13
ClinPred		0.017	T
GERP RS		-2.5
Varity_R		0.024
gMVP		0.14
Mutation Taster		=98/2	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs764095767; hg19: chr22-26688600; COSMIC: COSV50657840;