rs972076408

Variant names:

• chr22-26169677-C-T
• rs972076408
• NM_021115.5:c.8C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021115.5(SEZ6L):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000611 in 1,309,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SEZ6L NM_021115.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0270
• Publications: 1 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]

ENSG00000229770 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050223142).

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.8C>T	p.Ala3Val	missense	Exon 1 of 17	NP_066938.2
	SEZ6L	NM_001184773.2		c.8C>T	p.Ala3Val	missense	Exon 1 of 17	NP_001171702.1	Q9BYH1-6
	SEZ6L	NM_001184774.2		c.8C>T	p.Ala3Val	missense	Exon 1 of 16	NP_001171703.1	Q9BYH1-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6L	ENST00000248933.11	TSL:1 MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 17	ENSP00000248933.6	Q9BYH1-1
	SEZ6L	ENST00000404234.7	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 17	ENSP00000384772.3	Q9BYH1-6
	SEZ6L	ENST00000629590.2	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 16	ENSP00000485720.1	Q9BYH1-7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151974 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 4 AN: 1157486 Hom.: 0 Cov.: 24 AF XY: 0.00000178 AC XY: 1 AN XY: 562398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000127 AC: 3 AN: 23636

American (AMR) AF: 0.00 AC: 0 AN: 13200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16854

East Asian (EAS) AF: 0.00 AC: 0 AN: 27000

South Asian (SAS) AF: 0.00 AC: 0 AN: 43242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3184

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957340

Other (OTH) AF: 0.0000215 AC: 1 AN: 46540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000135934), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151974 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74234

African (AFR) AF: 0.0000966 AC: 4 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

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	Uncertain	0.41
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.027
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.079
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.087
MutPred		0.19		Loss of helix (P = 0.0444)
MVP		0.043
MPC		0.099
ClinPred		0.086	T
GERP RS		0.87
PromoterAI		-0.070	Neutral
Varity_R		0.030
gMVP		0.26
Mutation Taster		=93/7	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

Other links and lift over

dbSNP: rs972076408; hg19: chr22-26565643;