chr2-166002585-T-G

Variant names:

• chr2-166002585-T-G
• rs1295072436
• NM_001165963.4:c.4171A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP6

The NM_001165963.4(SCN1A):​c.4171A>C​(p.Asn1391His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1391S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.73
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166002584-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 449374.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• BP6: Variant 2-166002585-T-G is Benign according to our data. Variant chr2-166002585-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449638.

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.4171A>C	p.Asn1391His	missense	Exon 24 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.4171A>C	p.Asn1391His	missense	Exon 23 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.4171A>C	p.Asn1391His	missense	Exon 22 of 27	NP_001340877.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.4171A>C	p.Asn1391His	missense	Exon 24 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.4171A>C	p.Asn1391His	missense	Exon 23 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.4138A>C	p.Asn1380His	missense	Exon 21 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151762 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250566 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460180 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726398

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.0000898 AC: 4 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110962

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151762 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74114

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.0000659 AC: 1 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67820

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	SCN1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.024	D
Polyphen		0.42	B
Vest4		0.70
MutPred		0.65		Loss of catalytic residue at N1391 (P = 0.053)
MVP		0.87
MPC		0.75
ClinPred		0.58	D
GERP RS		4.3
Varity_R		0.35
gMVP		0.93
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1295072436; hg19: chr2-166859095;