22-26292616-T-C

Variant names:

• chr22-26292616-T-C
• rs760566198
• NM_021115.5:c.305T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021115.5(SEZ6L):​c.305T>C​(p.Leu102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,256 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SEZ6L NM_021115.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07964423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEZ6L	NM_021115.5	c.305T>C	p.Leu102Pro	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.305T>C	p.Leu102Pro	missense_variant	Exon 2 of 17	1	NM_021115.5	ENSP00000248933.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248778 AF XY: 0.0000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461106 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726790

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33462

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44666

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

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39680

Gnomad4 SAS exome AF: 0.000244 AC: 21 AN: 86106

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53192

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111762

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.305T>C (p.L102P) alteration is located in exon 2 (coding exon 2) of the SEZ6L gene. This alteration results from a T to C substitution at nucleotide position 305, causing the leucine (L) at amino acid position 102 to be replaced by a proline (P). 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	0.061
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.62	T;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.080	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N;.;N;N
REVEL	Benign	0.024
Sift	Uncertain	0.0090	D;D;D;.;D;D
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.61, 0.90, 0.0030	.;P;P;.;B;P
Vest4		0.16
MutPred		0.15		Gain of glycosylation at L102 (P = 0.0108);Gain of glycosylation at L102 (P = 0.0108);Gain of glycosylation at L102 (P = 0.0108);Gain of glycosylation at L102 (P = 0.0108);Gain of glycosylation at L102 (P = 0.0108);Gain of glycosylation at L102 (P = 0.0108);
MVP		0.082
MPC		0.26
ClinPred		0.054	T
GERP RS		-0.96
Varity_R		0.26
gMVP		0.37
Mutation Taster		=96/4	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: rs760566198; hg19: chr22-26688582;