12-51806345-G-T

Variant names:

• chr12-51806345-G-T
• rs869312966
• NM_001330260.2:c.4859G>T
• SCN8A p.Arg1620Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_StrongPP5_Strong

The NM_001330260.2(SCN8A):c.4859G>T (p.Arg1620Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005327903: Published functional studies demonstrate a damaging effect indicating that the R1620L variant reduces sodium current density and decreases neuronal firing (Liu et al., 2019)" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R1620P: Pathogenic (ClinVar VariationId 4812133, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1620*: Uncertain_significance (ClinVar VariationId 2784669, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 10 publications found

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

SCN8A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Specifications for SCN8A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005327903: Published functional studies demonstrate a damaging effect indicating that the R1620L variant reduces sodium current density and decreases neuronal firing (Liu et al., 2019); PMID: 30615093, 28330790
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 18 pathogenic, 0 benign (OR vs. background: 185.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R1620P: Pathogenic (ClinVar VariationId 4812133, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R1620*: Uncertain_significance (ClinVar VariationId 2784669, 1 star)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 10.451). ClinVar shows strong pathogenic missense enrichment: 333 P/LP and 85 B/LB missense entries (ratio 3.9×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN8A NM_001330260.2	MANE Select	c.4859G>T p.Arg1620Leu	missense	Exon 27 of 27	Prot: NP_001317189.1 UniProt:
	SCN8A NM_014191.4	MANE Plus Clinical	c.4859G>T p.Arg1620Leu	missense	Exon 27 of 27	Prot: NP_055006.1 UniProt:
	SCN8A NM_001177984.3		c.4736G>T p.Arg1579Leu	missense	Exon 26 of 26	Prot: NP_001171455.1 UniProt:

SCN8A NM_001330260.2

MANE Select

HGVSc / HGVSpc.4859G>Tp.Arg1620Leu

Exon rankExon 27 of 27

missense

Prot: NP_001317189.1UniProt: Q9UQD0-2

SCN8A NM_014191.4

MANE Plus Clinical

HGVSc / HGVSpc.4859G>Tp.Arg1620Leu

Exon rankExon 27 of 27

missense

Prot: NP_055006.1UniProt: Q9UQD0-1

SCN8A NM_001177984.3

HGVSc / HGVSpc.4736G>Tp.Arg1579Leu

Exon rankExon 26 of 26

missense

Prot: NP_001171455.1UniProt: Q9UQD0-5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN8A ENST00000354534.11	TSL:1MANE Plus Clinical	c.4859G>T p.Arg1620Leu	missense	Exon 27 of 27	Prot: ENSP00000346534.4 UniProt:
	SCN8A ENST00000627620.5	TSL:5MANE Select	c.4859G>T p.Arg1620Leu	missense	Exon 27 of 27	Prot: ENSP00000487583.2 UniProt:
	SCN8A ENST00000599343.5	TSL:5	c.4892G>T p.Arg1631Leu	missense	Exon 26 of 26	Prot: ENSP00000476447.3 UniProt:

SCN8A ENST00000354534.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.4859G>Tp.Arg1620Leu

Exon rankExon 27 of 27

missense

Prot: ENSP00000346534.4UniProt: Q9UQD0-1

SCN8A ENST00000627620.5

TSL:5MANE Select

HGVSc / HGVSpc.4859G>Tp.Arg1620Leu

Exon rankExon 27 of 27

missense

Prot: ENSP00000487583.2UniProt: Q9UQD0-2

SCN8A ENST00000599343.5

TSL:5

HGVSc / HGVSpc.4892G>Tp.Arg1631Leu

Exon rankExon 26 of 26

missense

Prot: ENSP00000476447.3UniProt: Q9UQD0-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	31
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.1	H
PhyloP100	Pathogenic	10
popEVE	Pathogenic	-5.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Varity_R	N/A	0.90
VESM-3B	Benign	-16

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs869312966;

hg19: chr12-52200129;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar