NM_178860.5:c.2822T>C

Variant names:

• chr17-28956377-A-G
• rs2040878737
• NM_178860.5:c.2822T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178860.5(SEZ6):​c.2822T>C​(p.Val941Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

SEZ6 (HGNC:15955): (seizure related 6 homolog) The protein encoded by this gene is thought to contain five cysteine-rich motifs that are similar to sushi domains, as well as two domains similar to the amino terminal half of the CUB (for complement C1r/C1s, Uegf, Bmp1) domain. Mutations in this gene have been associated with febrile seizures. [provided by RefSeq, Jul 2016]

PIPOX (HGNC:17804): (pipecolic acid and sarcosine oxidase) Enables L-pipecolate oxidase activity and sarcosine oxidase activity. Involved in L-lysine catabolic process to acetyl-CoA via L-pipecolate. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

LOC105371716 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19657522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEZ6	NM_178860.5	c.2822T>C	p.Val941Ala	missense_variant	Exon 15 of 17	ENST00000317338.17	NP_849191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17	c.2822T>C	p.Val941Ala	missense_variant	Exon 15 of 17	1	NM_178860.5	ENSP00000312942.11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2822T>C (p.V941A) alteration is located in exon 15 (coding exon 15) of the SEZ6 gene. This alteration results from a T to C substitution at nucleotide position 2822, causing the valine (V) at amino acid position 941 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	.;T;T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0042
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.36	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;.;.;.;.
REVEL	Benign	0.087
Sift	Benign	0.041	D;.;.;.;.
Sift4G	Uncertain	0.045	D;D;T;T;D
Polyphen		0.0010	B;.;B;.;.
Vest4		0.11
MutPred		0.53		Loss of stability (P = 0.0419);.;Loss of stability (P = 0.0419);Loss of stability (P = 0.0419);.;
MVP		0.35
MPC		0.32
ClinPred		0.52	D
GERP RS		4.5
Varity_R		0.080
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2040878737; hg19: chr17-27283395;