rs35735053

Variant names:

• chr2-165991411-A-G
• rs35735053
• NM_001165963.4:c.5864T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-165991411-A-G
• chr2-165991411-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001165963.4(SCN1A):​c.5864T>C​(p.Ile1955Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,784 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1955M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (16 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.39
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -19 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004661292).
• BP6: Variant 2-165991411-A-G is Benign according to our data. Variant chr2-165991411-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0082 (1247/152158) while in subpopulation AFR AF = 0.0288 (1194/41530). AF 95% confidence interval is 0.0274. There are 20 homozygotes in GnomAd4. There are 564 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1247 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.5864T>C	p.Ile1955Thr	missense	Exon 29 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.5864T>C	p.Ile1955Thr	missense	Exon 28 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.5864T>C	p.Ile1955Thr	missense	Exon 27 of 27	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.5864T>C	p.Ile1955Thr	missense	Exon 29 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.5864T>C	p.Ile1955Thr	missense	Exon 28 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.5831T>C	p.Ile1944Thr	missense	Exon 26 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.00819 AC: 1245 AN: 152040 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00194 AC: 486 AN: 250704 AF XY: 0.00153

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000804 AC: 1175 AN: 1461626 Hom.: 16 Cov.: 31 AF XY: 0.000700 AC XY: 509 AN XY: 727114

African (AFR) AF: 0.0303 AC: 1015 AN: 33464

American (AMR) AF: 0.00110 AC: 49 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111858

Other (OTH) AF: 0.00152 AC: 92 AN: 60390

GnomAD4 genome AF: 0.00820 AC: 1247 AN: 152158 Hom.: 20 Cov.: 32 AF XY: 0.00758 AC XY: 564 AN XY: 74388

African (AFR) AF: 0.0288 AC: 1194 AN: 41530

American (AMR) AF: 0.00275 AC: 42 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00318 Hom.: 15

Bravo AF: 0.00954

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.59
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.16	N
PhyloP100		4.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.33
Sift	Benign	0.48	T
Sift4G	Benign	0.57	T
Polyphen		0.0020	B
Vest4		0.082
MVP		0.23
MPC		0.91
ClinPred		0.0070	T
GERP RS		4.5
Varity_R		0.095
gMVP		0.17
Mutation Taster		=98/2	polymorphism

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: rs35735053; hg19: chr2-166847921; COSMIC: COSV99066807; COSMIC: COSV99066807;