2-165990220-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001165963.4(SCN1A):c.*1025T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.137 in 152,572 control chromosomes in the GnomAD database, including 1,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1820 hom., cov: 32)
  • Exomes 𝑓: 0.22 (11 hom.)
• Consequence: SCN1A NM_001165963.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 3.89

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-165990220-A-G is Benign according to our data. Variant chr2-165990220-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 331869.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.*1025T>C		3_prime_UTR_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-25393A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.*1025T>C		3_prime_UTR_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-25393A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20843 AN: 152018 Hom.: 1818 Cov.: 32

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.222 AC: 97 AN: 436 Hom.: 11 Cov.: 0 AF XY: 0.242 AC XY: 64 AN XY: 264

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.137 AC: 20865 AN: 152136 Hom.: 1820 Cov.: 32 AF XY: 0.144 AC XY: 10681 AN XY: 74368

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.0596

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.118

Alfa AF: 0.140 Hom.: 2263

Bravo AF: 0.139

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Migraine, familial hemiplegic, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Generalized epilepsy with febrile seizures plus, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs10497275; hg19: chr2-166846730; COSMIC: COSV57686375; COSMIC: COSV57686375;