chr16-29873724-T-C

Variant names:

• chr16-29873724-T-C
• rs368303260
• NM_001243332.2:c.2110A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001243332.2(SEZ6L2):​c.2110A>G​(p.Thr704Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T704S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEZ6L2 NM_001243332.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.16
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24783838).

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.2110A>G	p.Thr704Ala	missense	Exon 13 of 18	NP_001230261.1	A0A087WYL5
	SEZ6L2	NM_201575.4		c.2110A>G	p.Thr704Ala	missense	Exon 13 of 17	NP_963869.2	Q6UXD5-1
	SEZ6L2	NM_001243333.2		c.1978A>G	p.Thr660Ala	missense	Exon 12 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.2110A>G	p.Thr704Ala	missense	Exon 13 of 18	ENSP00000481917.1	A0A087WYL5
	SEZ6L2	ENST00000308713.9	TSL:1	c.2110A>G	p.Thr704Ala	missense	Exon 13 of 17	ENSP00000312550.5	Q6UXD5-1
	SEZ6L2	ENST00000350527.7	TSL:1	c.1900A>G	p.Thr634Ala	missense	Exon 13 of 18	ENSP00000310206.3	Q6UXD5-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425504 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 705902

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 42322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24168

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 82338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095430

Other (OTH) AF: 0.00 AC: 0 AN: 59052

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.060
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.78	N
PhyloP100		2.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.098
Sift	Benign	0.086	T
Sift4G	Benign	0.23	T
Polyphen		0.68	P
Vest4		0.41
MutPred		0.53		Loss of glycosylation at T704 (P = 0.053)
MVP		0.45
MPC		0.35
ClinPred		0.69	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.37
Mutation Taster		=67/33	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: rs368303260; hg19: chr16-29885045;