16-29873251-G-T

Variant names:

• chr16-29873251-G-T
• NM_001243332.2:c.2477C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001243332.2(SEZ6L2):​c.2477C>A​(p.Pro826Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEZ6L2 NM_001243332.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

SEZ6L2 (HGNC:30844): (seizure related 6 homolog like 2) This gene encodes a seizure-related protein that is localized on the cell surface. The gene is located in a region of chromosome 16p11.2 that is thought to contain candidate genes for autism spectrum disorders (ASD), though there is no evidence directly implicating this gene in ASD. Increased expression of this gene has been found in lung cancers, and the protein is therefore considered to be a novel prognostic marker for lung cancer. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243332.2. 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
	SEZ6L2	NM_001243332.2	MANE Select	c.2477C>A	p.Pro826Gln	missense	Exon 14 of 18	NP_001230261.1	A0A087WYL5
	SEZ6L2	NM_201575.4		c.2477C>A	p.Pro826Gln	missense	Exon 14 of 17	NP_963869.2	Q6UXD5-1
	SEZ6L2	NM_001243333.2		c.2345C>A	p.Pro782Gln	missense	Exon 13 of 17	NP_001230262.1	Q6UXD5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEZ6L2	ENST00000617533.5	TSL:1 MANE Select	c.2477C>A	p.Pro826Gln	missense	Exon 14 of 18	ENSP00000481917.1	A0A087WYL5
	SEZ6L2	ENST00000308713.9	TSL:1	c.2477C>A	p.Pro826Gln	missense	Exon 14 of 17	ENSP00000312550.5	Q6UXD5-1
	SEZ6L2	ENST00000350527.7	TSL:1	c.2267C>A	p.Pro756Gln	missense	Exon 14 of 18	ENSP00000310206.3	Q6UXD5-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.83		Loss of glycosylation at P826 (P = 0.0175)
MVP		0.80
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.92

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

hg19: chr16-29884572;