2-166048937-AAAT-A

Position:

• chr2-166048937-AAAT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.974_976delATT​(p.Tyr325del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.21

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001165963.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-166048937-AAAT-A is Pathogenic according to our data. Variant chr2-166048937-AAAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 503736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.974_976delATT	p.Tyr325del	disruptive_inframe_deletion	10/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.974_976delATT	p.Tyr325del	disruptive_inframe_deletion	10/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.974_976delATT	p.Tyr325del	disruptive_inframe_deletion	9/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.974_976delATT	p.Tyr325del	disruptive_inframe_deletion	7/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.974_976delATT	p.Tyr325del	disruptive_inframe_deletion	7/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2017

The c.974_976delATT variant in the SCN1A gene has been reported previously as de novo in an individual with Dravet syndrome (Wu et al., 2015). This variant causes an in-frame deletion of codon Tyrosine 325, denoted p.Tyr325del. This lost residue is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The c.974_976delATT variant is not observed in large population cohorts (Lek et al., 2016). Therefore, we interpret c.974_976delATT as a pathogenic variant. -

Obesity;C0036572:Seizure;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553548194; hg19: chr2-166905447;