rs140731963

Variant names:

• chr2-166012239-G-A
• rs140731963
• NM_001165963.4:c.3749C>T
• SCN1A p.Thr1250Met

Variant summary

Our verdict is Benign. The variant received -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. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• 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:8
• Conservation: PhyloP100: 4.01
• 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

Specifications for SCN1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 2 benign, 9 uncertain in NM_001165963.4
• 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 generalized epilepsy with febrile seizures plus, type 2, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, Lennox-Gastaut syndrome, malignant migrating partial seizures of infancy, Dravet syndrome, myoclonic-astatic epilepsy, familial or sporadic hemiplegic migraine, migraine, familial hemiplegic, 3, genetic developmental and epileptic encephalopathy, arthrogryposis.
• 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 Benign/Likely_benign. ClinVar VariationId is 206807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 37 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.3749C>T	p.Thr1250Met	missense	Exon 22 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3749C>T	p.Thr1250Met	missense	Exon 21 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3749C>T	p.Thr1250Met	missense	Exon 20 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.3749C>T	p.Thr1250Met	missense	Exon 22 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3749C>T	p.Thr1250Met	missense	Exon 21 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3716C>T	p.Thr1239Met	missense	Exon 19 of 26	ENSP00000364554.3	P35498-2

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

GnomAD2 exomes AF: 0.000405 AC: 101 AN: 249310 AF XY: 0.000401

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 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

African (AFR) AF: 0.0000900 AC: 3 AN: 33338

American (AMR) AF: 0.000157 AC: 7 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86146

European-Finnish (FIN) AF: 0.00311 AC: 166 AN: 53324

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1109622

Other (OTH) AF: 0.000216 AC: 13 AN: 60186

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41396

American (AMR) AF: 0.0000661 AC: 1 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67396

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SCN1A-related disorder (1)
-	-	1	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.053	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.10	T
Varity_R		0.18
gMVP		0.86
Mutation Taster		=34/66	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

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