chr2-165994267-A-G

Variant names:

• chr2-165994267-A-G
• rs145296488
• NM_001165963.4:c.4731T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.4731T>C​(p.Asn1577Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.10
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-165994267-A-G is Benign according to our data. Variant chr2-165994267-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93655.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (167/152028) while in subpopulation NFE AF = 0.00171 (116/67954). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 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.4731T>C	p.Asn1577Asn	synonymous	Exon 28 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.4731T>C	p.Asn1577Asn	synonymous	Exon 27 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.4731T>C	p.Asn1577Asn	synonymous	Exon 26 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.4731T>C	p.Asn1577Asn	synonymous	Exon 28 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.4731T>C	p.Asn1577Asn	synonymous	Exon 27 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.4698T>C	p.Asn1566Asn	synonymous	Exon 25 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00129 AC: 322 AN: 250582 AF XY: 0.00132

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00147 AC: 2154 AN: 1461130 Hom.: 3 Cov.: 31 AF XY: 0.00146 AC XY: 1058 AN XY: 726868

African (AFR) AF: 0.000120 AC: 4 AN: 33444

American (AMR) AF: 0.000291 AC: 13 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86232

European-Finnish (FIN) AF: 0.00298 AC: 159 AN: 53388

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00162 AC: 1796 AN: 1111576

Other (OTH) AF: 0.00128 AC: 77 AN: 60334

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74240

African (AFR) AF: 0.000314 AC: 13 AN: 41436

American (AMR) AF: 0.000788 AC: 12 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 67954

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00113

EpiCase AF: 0.00158

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Generalized epilepsy with febrile seizures plus, type 2 (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	1	-	Epilepsy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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: rs145296488; hg19: chr2-166850777;