chr12-51768899-CC-TT

Variant names:

• chr12-51768899-CC-TT
• NM_001330260.2:c.2936_2937delCCinsTT
• SCN8A p.Ser979Phe

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS1PM1PM2PM5PP2

The NM_001330260.2(SCN8A):c.2936_2937delCCinsTT (p.Ser979Phe) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S979N: Likely_pathogenic (ClinVar VariationId 2582519, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 1 star).
	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: 8 pathogenic, 0 benign (OR vs. background: 85.0).
	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.S979N: Likely_pathogenic (ClinVar VariationId 2582519, 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×).

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.2936_2937delCCinsTT p.Ser979Phe	missense	N/A	Prot: NP_001317189.1 UniProt:
	SCN8A NM_014191.4	MANE Plus Clinical	c.2936_2937delCCinsTT p.Ser979Phe	missense	N/A	Prot: NP_055006.1 UniProt:
	SCN8A NM_001177984.3		c.2936_2937delCCinsTT p.Ser979Phe	missense	N/A	Prot: NP_001171455.1 UniProt:

SCN8A NM_001330260.2

MANE Select

HGVSc / HGVSpc.2936_2937delCCinsTTp.Ser979Phe

Exon rankN/A

missense

Prot: NP_001317189.1UniProt: Q9UQD0-2

SCN8A NM_014191.4

MANE Plus Clinical

HGVSc / HGVSpc.2936_2937delCCinsTTp.Ser979Phe

Exon rankN/A

missense

Prot: NP_055006.1UniProt: Q9UQD0-1

SCN8A NM_001177984.3

HGVSc / HGVSpc.2936_2937delCCinsTTp.Ser979Phe

Exon rankN/A

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.2936_2937delCCinsTT p.Ser979Phe	missense	N/A	Prot: ENSP00000346534.4 UniProt:
	SCN8A ENST00000627620.5	TSL:5MANE Select	c.2936_2937delCCinsTT p.Ser979Phe	missense	N/A	Prot: ENSP00000487583.2 UniProt:
	SCN8A ENST00000599343.5	TSL:5	c.2969_2970delCCinsTT p.Ser990Phe	missense	N/A	Prot: ENSP00000476447.3 UniProt:

SCN8A ENST00000354534.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.2936_2937delCCinsTTp.Ser979Phe

Exon rankN/A

missense

Prot: ENSP00000346534.4UniProt: Q9UQD0-1

SCN8A ENST00000627620.5

TSL:5MANE Select

HGVSc / HGVSpc.2936_2937delCCinsTTp.Ser979Phe

Exon rankN/A

missense

Prot: ENSP00000487583.2UniProt: Q9UQD0-2

SCN8A ENST00000599343.5

TSL:5

HGVSc / HGVSpc.2969_2970delCCinsTTp.Ser990Phe

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr12-52162683;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar