rs140731963

chr2-166012239-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001165963.4(SCN1A):c.3749C>T(p.Thr1250Met) variant causes a missense change. The variant allele was found at a frequency of 0.000246 in 1,609,596 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1250T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.01

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)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001165963.4
• PP2: Missense variant where missense usually causes diseases, SCN1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.053359985).
• BP6: Variant 2-166012239-G-A is Benign according to our data. Variant chr2-166012239-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 206807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.3749C>T	p.Thr1250Met	missense_variant	22/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-3374G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.3749C>T	p.Thr1250Met	missense_variant	22/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-3374G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000245 AC: 37 AN: 151114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000405 AC: 101 AN: 249310 Hom.: 0 AF XY: 0.000401 AC XY: 54 AN XY: 134820

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1458364 Hom.: 1 Cov.: 30 AF XY: 0.000252 AC XY: 183 AN XY: 725490

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000245 AC: 37 AN: 151232 Hom.: 0 Cov.: 32 AF XY: 0.000311 AC XY: 23 AN XY: 73902

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000363 AC: 44

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2019	This variant is associated with the following publications: (PMID: 27231140, 19522081, 21719429, 28202706, 28150151, 26990884, 31009440) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	SCN1A: PP2, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 10, 2023

Variant summary: SCN1A c.3749C>T (p.Thr1250Met) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 249310 control chromosomes. The observed variant frequency is approximately 23-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is benign. c.3749C>T has been reported in the literature in individuals affected with Seizure Disorders, without evidence for causality (i.e. lack of segregation or segregation data not provided) and in one case where the variant co-occurred with a pathogenic variant (c.3706-2A>G), providing supporting evidence for a benign role (e.g. Orrico_2009, Catarino_2011, Lal_2016, Fang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21719429, 19522081, 31009440, 26990884). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either benign (n=2)/likely benign (n=1), or VUS (=1). Based on the evidence outlined above, the variant was classified as benign. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2021

- -

SCN1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe myoclonic epilepsy in infancy Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;D;.;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.74	T
Polyphen		0.013, 0.60	.;.;.;B;P;.;B;P;P;.
Vest4		0.50, 0.51, 0.48, 0.51
MVP		0.99
MPC		1.0
ClinPred		0.057	T
GERP RS		4.4
Varity_R		0.18
gMVP		0.86

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: rs140731963; hg19: chr2-166868749; COSMIC: COSV57665739; COSMIC: COSV57665739;