12-51769235-A-C

Variant names:

• chr12-51769235-A-C
• rs558738676
• NM_001330260.2:c.3272A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001330260.2(SCN8A):​c.3272A>C​(p.Asn1091Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.33

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• 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, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35739303).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 17 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.3305A>C	p.Asn1102Thr	missense_variant	Exon 16 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.3272A>C	p.Asn1091Thr	missense_variant	Exon 16 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250140 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135334

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74300

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3272A>C (p.N1091T) alteration is located in exon 17 (coding exon 16) of the SCN8A gene. This alteration results from a A to C substitution at nucleotide position 3272, causing the asparagine (N) at amino acid position 1091 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1091 of the SCN8A protein (p.Asn1091Thr). This variant is present in population databases (rs558738676, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 858739). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN8A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;.;T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Uncertain	2.2	M;M;M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;D;N;.;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D;D;.;.
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.47	P;.;.;.;.
Vest4		0.38
MutPred		0.40		Gain of glycosylation at N1091 (P = 0.0357);Gain of glycosylation at N1091 (P = 0.0357);Gain of glycosylation at N1091 (P = 0.0357);.;Gain of glycosylation at N1091 (P = 0.0357);
MVP		0.78
MPC		1.5
ClinPred		0.62	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs558738676; hg19: chr12-52163019;