rs527371769

Variant names:

• chr22-26169713-C-A
• rs527371769
• NM_021115.5:c.44C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-26169713-C-A
• chr22-26169713-C-G
• chr22-26169713-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021115.5(SEZ6L):​c.44C>A​(p.Ser15*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000087 in 1,149,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: SEZ6L NM_021115.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• 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]

ENSG00000229770 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.44C>A	p.Ser15*	stop_gained	Exon 1 of 17	NP_066938.2
	SEZ6L	NM_001184773.2		c.44C>A	p.Ser15*	stop_gained	Exon 1 of 17	NP_001171702.1	Q9BYH1-6
	SEZ6L	NM_001184774.2		c.44C>A	p.Ser15*	stop_gained	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.44C>A	p.Ser15*	stop_gained	Exon 1 of 17	ENSP00000248933.6	Q9BYH1-1
	SEZ6L	ENST00000404234.7	TSL:1	c.44C>A	p.Ser15*	stop_gained	Exon 1 of 17	ENSP00000384772.3	Q9BYH1-6
	SEZ6L	ENST00000629590.2	TSL:1	c.44C>A	p.Ser15*	stop_gained	Exon 1 of 16	ENSP00000485720.1	Q9BYH1-7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.70e-7 AC: 1 AN: 1149260 Hom.: 0 Cov.: 29 AF XY: 0.00000180 AC XY: 1 AN XY: 554248

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

African (AFR) AF: 0.00 AC: 0 AN: 23440

American (AMR) AF: 0.00 AC: 0 AN: 9992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15714

East Asian (EAS) AF: 0.00 AC: 0 AN: 27042

South Asian (SAS) AF: 0.00 AC: 0 AN: 38276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3100

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 960062

Other (OTH) AF: 0.00 AC: 0 AN: 46196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.35	N
PhyloP100		-0.15
Vest4		0.18
GERP RS		3.7
PromoterAI		-0.016	Neutral
Mutation Taster		=19/181	disease causing (fs/PTC)

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: rs527371769; hg19: chr22-26565679;