rs780607306

Variant names:

• chr2-166013893-C-A
• rs780607306
• NM_001165963.4:c.3556G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166013893-C-A
• chr2-166013893-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_001165963.4(SCN1A):​c.3556G>T​(p.Val1186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V1186I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.33
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 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.
• BP6: Variant 2-166013893-C-A is Benign according to our data. Variant chr2-166013893-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206804.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAdExome4 at 14 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3556G>T	p.Val1186Leu	missense_variant	Exon 21 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3556G>T	p.Val1186Leu	missense_variant	Exon 21 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3556G>T	p.Val1186Leu	missense_variant	Exon 20 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3523G>T	p.Val1175Leu	missense_variant	Exon 18 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.3472G>T	p.Val1158Leu	missense_variant	Exon 20 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.0000399 AC: 10 AN: 250334 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

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: 0.000327

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459490 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726060

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110610

Other (OTH) AF: 0.0000663 AC: 4 AN: 60306

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151690 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74082

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.000132 AC: 2 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67726

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 06, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the SCN1A gene. The V1186L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1186L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters a position where amino acids with similar properties to Valine are tolerated across species, and is predicted to be within the cytoplasmic loop between 2nd and 3rd homologous domains. However, the V1186L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Inborn genetic diseases Benign:1

Nov 18, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;T;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.;M;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.36	.;.;.;T;.;.;T;.;T;T
Polyphen		0.0050, 0.0090	.;.;.;B;B;.;B;B;B;.
Vest4		0.65, 0.65, 0.64, 0.64
MutPred		0.67		.;Gain of catalytic residue at V1186 (P = 0.0205);.;Gain of catalytic residue at V1186 (P = 0.0205);.;.;Gain of catalytic residue at V1186 (P = 0.0205);.;.;.;
MVP		0.83
MPC		1.4
ClinPred		0.24	T
GERP RS		5.8
Varity_R		0.60
gMVP		0.89
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780607306; hg19: chr2-166870403;