chr2-166012265-A-G

Variant names:

• chr2-166012265-A-G
• rs36031496
• NM_001165963.4:c.3723T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001165963.4(SCN1A):​c.3723T>C​(p.Tyr1241Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,608,278 control chromosomes in the GnomAD database, including 601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (303 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (298 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.24
• 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)

LOC102724058 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-166012265-A-G is Benign according to our data. Variant chr2-166012265-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

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.3723T>C	p.Tyr1241Tyr	synonymous	Exon 22 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3723T>C	p.Tyr1241Tyr	synonymous	Exon 21 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3723T>C	p.Tyr1241Tyr	synonymous	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.3723T>C	p.Tyr1241Tyr	synonymous	Exon 22 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3723T>C	p.Tyr1241Tyr	synonymous	Exon 21 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3690T>C	p.Tyr1230Tyr	synonymous	Exon 19 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5248 AN: 151236 Hom.: 301 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000430

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.00904 AC: 2242 AN: 248006 AF XY: 0.00632

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00354 AC: 5155 AN: 1456924 Hom.: 298 Cov.: 30 AF XY: 0.00297 AC XY: 2156 AN XY: 724810

African (AFR) AF: 0.123 AC: 4081 AN: 33270

American (AMR) AF: 0.00721 AC: 320 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.0000770 AC: 2 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86068

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53302

Middle Eastern (MID) AF: 0.00732 AC: 42 AN: 5736

European-Non Finnish (NFE) AF: 0.000197 AC: 218 AN: 1108572

Other (OTH) AF: 0.00784 AC: 471 AN: 60098

GnomAD4 genome AF: 0.0347 AC: 5257 AN: 151354 Hom.: 303 Cov.: 32 AF XY: 0.0335 AC XY: 2481 AN XY: 74010

African (AFR) AF: 0.121 AC: 4997 AN: 41412

American (AMR) AF: 0.0127 AC: 192 AN: 15152

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000430 AC: 29 AN: 67438

Other (OTH) AF: 0.0176 AC: 37 AN: 2104

Alfa AF: 0.0167 Hom.: 88

Bravo AF: 0.0395

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (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)
-	-	1	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.3
DANN	Benign	0.56
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs36031496; hg19: chr2-166868775; COSMIC: COSV57683516; COSMIC: COSV57683516;