rs201870762

Variant names:

• chr2-166048914-G-C
• rs201870762
• NM_001165963.4:c.1000C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-166048914-G-C
• chr2-166048914-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1 PM5 PP2 BP4_Strong BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.1000C>G​(p.Leu334Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,606,378 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L334P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.966
• Publications: 5 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)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001165963.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166048913-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 581861.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.029185712).
• BP6: Variant 2-166048914-G-C is Benign according to our data. Variant chr2-166048914-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206934.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00027 (41/151882) while in subpopulation AMR AF = 0.000919 (14/15226). AF 95% confidence interval is 0.000555. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 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.1000C>G	p.Leu334Val	missense	Exon 10 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.1000C>G	p.Leu334Val	missense	Exon 9 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.1000C>G	p.Leu334Val	missense	Exon 8 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.1000C>G	p.Leu334Val	missense	Exon 10 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.1000C>G	p.Leu334Val	missense	Exon 9 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.1000C>G	p.Leu334Val	missense	Exon 7 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000339 AC: 85 AN: 250382 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000142 AC: 206 AN: 1454496 Hom.: 0 Cov.: 29 AF XY: 0.000144 AC XY: 104 AN XY: 724066

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.000560 AC: 25 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 130 AN: 26010

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39484

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1105822

Other (OTH) AF: 0.000483 AC: 29 AN: 60068

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74130

African (AFR) AF: 0.0000483 AC: 2 AN: 41372

American (AMR) AF: 0.000919 AC: 14 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67940

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000461

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.029	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.97
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.64
MVP		0.97
MPC		1.7
ClinPred		0.12	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.93
Mutation Taster		=4/96	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

Other links and lift over

dbSNP: rs201870762; hg19: chr2-166905424;