rs145101180

Variant names:

• chr2-166039591-G-A
• rs145101180
• NM_001165963.4:c.2421C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001165963.4(SCN1A):​c.2421C>T​(p.Phe807Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,352 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (10 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.84
• Publications: 3 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

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-166039591-G-A is Benign according to our data. Variant chr2-166039591-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000841 (128/152138) while in subpopulation SAS AF = 0.00749 (36/4806). AF 95% confidence interval is 0.00556. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 128 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.2421C>T	p.Phe807Phe	synonymous	Exon 17 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.2421C>T	p.Phe807Phe	synonymous	Exon 16 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.2421C>T	p.Phe807Phe	synonymous	Exon 15 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.2421C>T	p.Phe807Phe	synonymous	Exon 17 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.2421C>T	p.Phe807Phe	synonymous	Exon 16 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.2388C>T	p.Phe796Phe	synonymous	Exon 14 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.000842 AC: 128 AN: 152024 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00171 AC: 429 AN: 250610 AF XY: 0.00212

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000724

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.00112 AC: 1635 AN: 1461214 Hom.: 10 Cov.: 36 AF XY: 0.00135 AC XY: 982 AN XY: 726952

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.000470 AC: 21 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 152 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00814 AC: 702 AN: 86212

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.000585 AC: 650 AN: 1111510

Other (OTH) AF: 0.00136 AC: 82 AN: 60366

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152138 Hom.: 1 Cov.: 31 AF XY: 0.00101 AC XY: 75 AN XY: 74370

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000982 AC: 15 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00749 AC: 36 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000737

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00101

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	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	0.12
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		1.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs145101180; hg19: chr2-166896101; COSMIC: COSV57672968; COSMIC: COSV57672968;