chr12-51769943-C-T

Variant names:

• chr12-51769943-C-T
• rs1555226280
• NM_001330260.2:c.3448C>T
• SCN8A p.Gln1150*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_001330260.2(SCN8A):c.3448C>T (p.Gln1150*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_001330260.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.89
• 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 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 18 of 27) at amino acid 1150 of 1980, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	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.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 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.3448C>T p.Gln1150*	stop_gained	Exon 18 of 27	Prot: NP_001317189.1 UniProt:
	SCN8A NM_014191.4	MANE Plus Clinical	c.3448C>T p.Gln1150*	stop_gained	Exon 18 of 27	Prot: NP_055006.1 UniProt:
	SCN8A NM_001177984.3		c.3448C>T p.Gln1150*	stop_gained	Exon 18 of 26	Prot: NP_001171455.1 UniProt:

SCN8A NM_001330260.2

MANE Select

HGVSc / HGVSpc.3448C>Tp.Gln1150*

Exon rankExon 18 of 27

stop_gained

Prot: NP_001317189.1UniProt: Q9UQD0-2

SCN8A NM_014191.4

MANE Plus Clinical

HGVSc / HGVSpc.3448C>Tp.Gln1150*

Exon rankExon 18 of 27

stop_gained

Prot: NP_055006.1UniProt: Q9UQD0-1

SCN8A NM_001177984.3

HGVSc / HGVSpc.3448C>Tp.Gln1150*

Exon rankExon 18 of 26

stop_gained

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.3448C>T p.Gln1150*	stop_gained	Exon 18 of 27	Prot: ENSP00000346534.4 UniProt:
	SCN8A ENST00000627620.5	TSL:5MANE Select	c.3448C>T p.Gln1150*	stop_gained	Exon 18 of 27	Prot: ENSP00000487583.2 UniProt:
	SCN8A ENST00000599343.5	TSL:5	c.3481C>T p.Gln1161*	stop_gained	Exon 17 of 26	Prot: ENSP00000476447.3 UniProt:

SCN8A ENST00000354534.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.3448C>Tp.Gln1150*

Exon rankExon 18 of 27

stop_gained

Prot: ENSP00000346534.4UniProt: Q9UQD0-1

SCN8A ENST00000627620.5

TSL:5MANE Select

HGVSc / HGVSpc.3448C>Tp.Gln1150*

Exon rankExon 18 of 27

stop_gained

Prot: ENSP00000487583.2UniProt: Q9UQD0-2

SCN8A ENST00000599343.5

TSL:5

HGVSc / HGVSpc.3481C>Tp.Gln1161*

Exon rankExon 17 of 26

stop_gained

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1454790	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000238	AC:6	Hom:0	AN:25252	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	39
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.33	N
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	6/194	disease causing (fs/PTC)
PhyloP100	Benign	1.9

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.060
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: rs1555226280;

hg19: chr12-52163727;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar