chr12-51705510-G-C

Variant names:

• chr12-51705510-G-C
• rs879255699
• NM_001330260.2:c.1228G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate

The ENST00000354534.11(SCN8A):​c.1228G>C​(p.Val410Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V410A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A ENST00000354534.11 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 10.0
• Publications: 6 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 Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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
• infantile convulsions and choreoathetosis

  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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript ENST00000354534.11 (SCN8A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000354534.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51705511-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1387304.
• PP2: Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.278 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354534.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.1228G>C	p.Val410Leu	missense	Exon 10 of 27	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.1228G>C	p.Val410Leu	missense	Exon 10 of 27	NP_055006.1
	SCN8A	NM_001177984.3		c.1228G>C	p.Val410Leu	missense	Exon 10 of 26	NP_001171455.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.1228G>C	p.Val410Leu	missense	Exon 10 of 27	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1228G>C	p.Val410Leu	missense	Exon 10 of 27	ENSP00000487583.2
	SCN8A	ENST00000599343.5	TSL:5	c.1228G>C	p.Val410Leu	missense	Exon 9 of 26	ENSP00000476447.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Developmental and epileptic encephalopathy, 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.076	T
Polyphen		0.031	B
Vest4		0.85
MutPred		0.58		Loss of catalytic residue at V410 (P = 0.0326)
MVP		0.95
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs879255699; hg19: chr12-52099294;