chr12-51706491-G-C

Variant names:

• chr12-51706491-G-C
• rs748156622
• NM_001330260.2:c.1411G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001330260.2(SCN8A):​c.1411G>C​(p.Gly471Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• 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 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: 10.436 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30628392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1411G>C	p.Gly471Arg	missense_variant	Exon 11 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1411G>C	p.Gly471Arg	missense_variant	Exon 10 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1411G>C	p.Gly471Arg	missense_variant	Exon 10 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454096 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722508

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 43638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 84468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108434

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.;.;.;.
Eigen	Benign	0.069
Eigen_PC	Benign	0.083
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.52	T;T;T;.;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	.;L;L;L;L;L;.
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	.;N;N;N;.;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.37	.;T;T;T;.;.;D
Sift4G	Benign	0.13	.;T;T;T;T;T;T
Polyphen		1.0, 0.57	.;D;.;.;P;.;.
Vest4		0.19, 0.20, 0.17, 0.22
MutPred		0.28		Gain of methylation at G471 (P = 0.0121);Gain of methylation at G471 (P = 0.0121);Gain of methylation at G471 (P = 0.0121);Gain of methylation at G471 (P = 0.0121);Gain of methylation at G471 (P = 0.0121);Gain of methylation at G471 (P = 0.0121);.;
MVP		0.77
MPC		2.3
ClinPred		0.73	D
GERP RS		4.4
Varity_R		0.074
gMVP		0.20
Mutation Taster		=77/23	polymorphism

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: rs748156622; hg19: chr12-52100275;