chr2-165989284-G-A

Variant names:

• chr2-165989284-G-A
• rs7577411
• NM_001165963.4:c.*1961C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.*1961C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 152,414 control chromosomes in the GnomAD database, including 1,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (1088 hom., cov: 32)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.22
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-165989284-G-A is Benign according to our data. Variant chr2-165989284-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 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.*1961C>T		3_prime_UTR	Exon 29 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.*1961C>T		3_prime_UTR	Exon 28 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.*1961C>T		3_prime_UTR	Exon 27 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.*1961C>T		3_prime_UTR	Exon 29 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.*1961C>T		3_prime_UTR	Exon 28 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.*1961C>T		3_prime_UTR	Exon 26 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12259 AN: 151864 Hom.: 1083 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0922

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00774

Gnomad OTH AF: 0.0565

GnomAD4 exome AF: 0.0139 AC: 6 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0192 AC XY: 5 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0141 AC: 6 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0809 AC: 12292 AN: 151982 Hom.: 1088 Cov.: 32 AF XY: 0.0810 AC XY: 6019 AN XY: 74284

African (AFR) AF: 0.206 AC: 8540 AN: 41416

American (AMR) AF: 0.149 AC: 2267 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.0922 AC: 474 AN: 5140

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4820

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10584

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00774 AC: 526 AN: 67990

Other (OTH) AF: 0.0554 AC: 117 AN: 2112

Alfa AF: 0.0386 Hom.: 1103

Bravo AF: 0.0982

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 2 (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs7577411; hg19: chr2-166845794;