rs1057518801

Variant names:

• chr2-165130238-A-G
• rs1057518801
• NM_006922.4:c.2624T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2_Supporting PS2 PM6 PS3

This summary comes from the ClinGen Evidence Repository: The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID:29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16043377/MONDO:0100062/069

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 7.47
• Publications: 15 publications found

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCN3A Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• developmental and epileptic encephalopathy, 62

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy, familial focal, with variable foci 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236283 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	NM_006922.4	MANE Select	c.2624T>C	p.Ile875Thr	missense	Exon 17 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.2477T>C	p.Ile826Thr	missense	Exon 17 of 28	NP_001075145.1
	SCN3A	NM_001081677.2		c.2477T>C	p.Ile826Thr	missense	Exon 17 of 28	NP_001075146.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.2624T>C	p.Ile875Thr	missense	Exon 17 of 28	ENSP00000283254.7
	SCN3A	ENST00000409101.7	TSL:1	c.2477T>C	p.Ile826Thr	missense	Exon 17 of 28	ENSP00000386726.3
	SCN3A	ENST00000706067.1		c.2573T>C	p.Ile858Thr	missense	Exon 17 of 28	ENSP00000516211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Developmental and epileptic encephalopathy, 62 (5)
3	-	-	not provided (3)
2	-	-	Developmental and epileptic encephalopathy (2)
2	-	-	Epilepsy, familial focal, with variable foci 4 (3)
1	-	-	Epilepsy (1)
1	-	-	Polymicrogyria;C0424605:Developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0229)
MVP		0.98
MPC		3.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1057518801; hg19: chr2-165986748; COSMIC: COSV51817927;