chr2-165991324-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PP2PP3BP4_ModerateBP6BS1BS2

The NM_001165963.4(SCN1A):c.5951C>A(p.Pro1984His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 9.62

Publications

4 publications found

Variant links:

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 links:

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

SCN1A-AS1 links:

LOC102724058 (HGNC:):

LOC102724058 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PP2

Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.11564532).

BP6

Variant 2-165991324-G-T is Benign according to our data. Variant chr2-165991324-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93661.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000683 (104/152192) while in subpopulation AFR AF = 0.00238 (99/41514). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 104 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.5951C>A	p.Pro1984His	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.5951C>A	p.Pro1984His	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.5951C>A	p.Pro1984His	missense_variant	Exon 28 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.5918C>A	p.Pro1973His	missense_variant	Exon 26 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.2 link	c.5867C>A	p.Pro1956His	missense_variant	Exon 28 of 28	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

AF:

0.000684

AC:

104

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000160

AC:

AN:

250738

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461266

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

33380

American (AMR)

AF:

0.0000673

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111786

Other (OTH)

AF:

0.0000331

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152192

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41514

American (AMR)

AF:

0.000327

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.000805

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SCN1A p.P1984H variant was not identified in the literature but was identified in dbSNP (ID: rs146733308) and ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, and Fulgent Genetics; as likely benign by Invitae; and as benign by Ambry Genetics). The variant was identified in control databases in 61 of 282118 chromosomes at a frequency of 0.0002162, and was observed at the highest frequency in the African population in 59 of 24952 chromosomes (freq: 0.002365) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant epilepsy with febrile seizures and early infantile epileptic encephalopathy conditions associated with SCN1A variants. The p.P1984 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Mar 30, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3

Uncertain:2

Jun 02, 2019

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SCN1A c.5951C>A (p.Pro1984His) variant identified substitutes a highly conserved Proline for Histidine at amino acid 1973/1999 (coding exon 29/29). In silico algorithms predict this variant to be Deleterious (Provean; score:-6.60) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. The c.5951C>A (p.Pro1984His) variant has been reported in ClinVar as a Variant of Uncertain Significance (VarID: 93661), and has been reported a single time in a large cohort study of pediatric patients with drug resistant epilepsy [PMID: 29353705], with no patient specific phenotype information. Given the lack of compelling information supporting its pathogenicity, the c.5951C>A (p.Pro1984His) variant identified in the SCN1A gene is reported here as a Variant of Uncertain Significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 07, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SCN1A-related disorder

Benign:1

May 23, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.0017

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

.;.;.;D;.;D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D;D;D;.;.;.;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;.;.;M;.;M;.;.;.

PhyloP100

9.6

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.6

.;.;.;D;.;D;.;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;.;.;D;.;D;.;D;D

Sift4G

Pathogenic

0.0

.;.;.;D;.;D;.;D;D

Polyphen

0.76

.;.;.;.;P;.;P;P;.

Vest4

0.55, 0.62, 0.61, 0.62

MVP

0.90

MPC

1.9

ClinPred

0.23

GERP RS

5.7

Varity_R

0.81

gMVP

0.50

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over