2-166037787-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):c.2935G>A(p.Gly979Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G979E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 7.89

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166037786-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 2-166037787-C-T is Pathogenic according to our data. Variant chr2-166037787-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2935G>A	p.Gly979Arg	missense_variant	18/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2935G>A	p.Gly979Arg	missense_variant	18/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+1657C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2017	The G979R pathogenic variant in the SCN1A gene has been previously reported in an individual with intractable childhood epilepsy with generlaized tonic-clonic seizures (ICEGTC) (Fujiwara et al., 2003). Functional studies have demonstrated that G979R leads to impaired channel function (Sugawara at al., 2003, Rhodes et al., 2005). The G979R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G979R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position predicted to be within the transmembrane segment S6 of the second homologous domain. Missense variants in nearby residues (M976I, V977M, V982L) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, this variant is classified as pathogenic and it's presence is consistent with the diagnosis in this individual. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Severe myoclonic epilepsy in infancy Other:2

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
Polyphen		1.0, 0.99	.;.;.;D;D;.;D;D;D;.
Vest4		0.97, 0.94, 0.96, 0.96
MutPred		0.86		.;Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);.;.;Gain of sheet (P = 0.0221);.;.;.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

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: rs121918754; hg19: chr2-166894297;