chr16-29876761-T-C

Variant names:

• chr16-29876761-T-C
• rs557575227
• NM_001243332.2:c.2099A>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.2099A>G​(p.Gln700Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000194 in 1,548,768 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. 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. Q700L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEZ6L2 NM_001243332.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70
• 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=0.11503366).

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.2099A>G	p.Gln700Arg	missense	Exon 12 of 18	NP_001230261.1	A0A087WYL5
	SEZ6L2	NM_201575.4		c.2099A>G	p.Gln700Arg	missense	Exon 12 of 17	NP_963869.2	Q6UXD5-1
	SEZ6L2	NM_001243333.2		c.1967A>G	p.Gln656Arg	missense	Exon 11 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.2099A>G	p.Gln700Arg	missense	Exon 12 of 18	ENSP00000481917.1	A0A087WYL5
	SEZ6L2	ENST00000308713.9	TSL:1	c.2099A>G	p.Gln700Arg	missense	Exon 12 of 17	ENSP00000312550.5	Q6UXD5-1
	SEZ6L2	ENST00000350527.7	TSL:1	c.1889A>G	p.Gln630Arg	missense	Exon 12 of 18	ENSP00000310206.3	Q6UXD5-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157174 AF XY: 0.00

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.0000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396562 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687978

African (AFR) AF: 0.00 AC: 0 AN: 31758

American (AMR) AF: 0.0000276 AC: 1 AN: 36256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25024

East Asian (EAS) AF: 0.00 AC: 0 AN: 35918

South Asian (SAS) AF: 0.00 AC: 0 AN: 79908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077250

Other (OTH) AF: 0.00 AC: 0 AN: 57750

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74436

African (AFR) AF: 0.0000241 AC: 1 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.00000869 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.14
Sift	Benign	0.036	D
Sift4G	Uncertain	0.041	D
Polyphen		0.84	P
Vest4		0.11
MutPred		0.51		Loss of ubiquitination at K701 (P = 0.0683)
MVP		0.60
MPC		0.46
ClinPred		0.34	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.66
Mutation Taster		=87/13	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: rs557575227; hg19: chr16-29888082;