chr2-166036376-A-G

Variant names:

• chr2-166036376-A-G
• rs121918818
• NM_001165963.4:c.3101T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001165963.4(SCN1A):​c.3101T>C​(p.Ile1034Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,601,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 9.32
• 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 -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02259159).
• BP6: Variant 2-166036376-A-G is Benign according to our data. Variant chr2-166036376-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000762 (116/152292) while in subpopulation AFR AF = 0.00279 (116/41568). AF 95% confidence interval is 0.00238. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 116 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.3101T>C	p.Ile1034Thr	missense	Exon 19 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3101T>C	p.Ile1034Thr	missense	Exon 18 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3101T>C	p.Ile1034Thr	missense	Exon 17 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.3101T>C	p.Ile1034Thr	missense	Exon 19 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3101T>C	p.Ile1034Thr	missense	Exon 18 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3068T>C	p.Ile1023Thr	missense	Exon 16 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000209 AC: 50 AN: 238888 AF XY: 0.000124

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.0000937

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: 0.0000780 AC: 113 AN: 1449262 Hom.: 0 Cov.: 35 AF XY: 0.0000639 AC XY: 46 AN XY: 720228

African (AFR) AF: 0.00308 AC: 100 AN: 32516

American (AMR) AF: 0.000166 AC: 7 AN: 42080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25488

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 83248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107904

Other (OTH) AF: 0.0000669 AC: 4 AN: 59774

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74460

African (AFR) AF: 0.00279 AC: 116 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000452 Hom.: 0

Bravo AF: 0.000922

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autism (1)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SCN1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		0.17	B
Vest4		0.67
MVP		0.74
MPC		1.2
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.41
gMVP		0.57
Mutation Taster		=8/92	disease causing

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: rs121918818; hg19: chr2-166892886;