2-166036571-G-A

Variant names:

• chr2-166036571-G-A
• rs7601520
• NM_001165963.4:c.2947-41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.2947-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 1,591,596 control chromosomes in the GnomAD database, including 398,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41729 hom., cov: 31)
  • Exomes 𝑓: 0.70 (357155 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.240
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-166036571-G-A is Benign according to our data. Variant chr2-166036571-G-A is described in ClinVar as Benign. ClinVar VariationId is 487362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.2947-41C>T		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.2947-41C>T		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.2947-41C>T		intron	N/A	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.2947-41C>T		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.2947-41C>T		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.2914-41C>T		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112008 AN: 151904 Hom.: 41684 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.724 AC: 170886 AN: 235970 AF XY: 0.714

Gnomad AFR exome AF: 0.828

Gnomad AMR exome AF: 0.808

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.895

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.702 AC: 1010489 AN: 1439574 Hom.: 357155 Cov.: 27 AF XY: 0.698 AC XY: 500452 AN XY: 716468

African (AFR) AF: 0.826 AC: 27036 AN: 32718

American (AMR) AF: 0.802 AC: 35254 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15580 AN: 25910

East Asian (EAS) AF: 0.895 AC: 35019 AN: 39132

South Asian (SAS) AF: 0.682 AC: 57756 AN: 84630

European-Finnish (FIN) AF: 0.748 AC: 39533 AN: 52840

Middle Eastern (MID) AF: 0.514 AC: 2847 AN: 5544

European-Non Finnish (NFE) AF: 0.690 AC: 756109 AN: 1095348

Other (OTH) AF: 0.695 AC: 41355 AN: 59490

GnomAD4 genome AF: 0.737 AC: 112114 AN: 152022 Hom.: 41729 Cov.: 31 AF XY: 0.741 AC XY: 55045 AN XY: 74296

African (AFR) AF: 0.823 AC: 34149 AN: 41506

American (AMR) AF: 0.742 AC: 11324 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2091 AN: 3470

East Asian (EAS) AF: 0.891 AC: 4594 AN: 5156

South Asian (SAS) AF: 0.709 AC: 3415 AN: 4816

European-Finnish (FIN) AF: 0.757 AC: 7989 AN: 10554

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46370 AN: 67944

Other (OTH) AF: 0.683 AC: 1441 AN: 2110

Alfa AF: 0.696 Hom.: 20343

Bravo AF: 0.740

Asia WGS AF: 0.790 AC: 2748 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 18, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported.

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		-0.24
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: rs7601520; hg19: chr2-166893081;