rs201458257

chr12-51794594-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1 PP2 BP4 BP6 BS1 BS2

The NM_014191.4(SCN8A):c.4748T>C(p.Ile1583Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000467 in 1,613,900 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1583V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 5.09

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 Benign. Variant got -7 ACMG points.

• PM1: In a repeat IV (size 297) in uniprot entity SCN8A_HUMAN there are 67 pathogenic changes around while only 13 benign (84%) in NM_014191.4
• PP2: Missense variant where missense usually causes diseases, SCN8A
• BP4: Computational evidence support a benign effect (MetaRNN=0.41254112).
• BP6: Variant 12-51794594-T-C is Benign according to our data. Variant chr12-51794594-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130248.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1}. Variant chr12-51794594-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000256 (39/152196) while in subpopulation NFE AF= 0.000485 (33/68026). AF 95% confidence interval is 0.000355. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4748T>C	p.Ile1583Thr	missense_variant	26/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4748T>C	p.Ile1583Thr	missense_variant	26/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4625T>C	p.Ile1542Thr	missense_variant	25/26
SCN8A	NM_001369788.1	c.4625T>C	p.Ile1542Thr	missense_variant	25/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4748T>C	p.Ile1583Thr	missense_variant	26/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4748T>C	p.Ile1583Thr	missense_variant	26/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000205 AC: 51 AN: 249166 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135186

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: 0.000186

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000488 AC: 714 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 342 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

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: 0.000150

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74358

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SCN8A: PP2, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 02, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32090326, 26220391, 33083721) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Developmental and epileptic encephalopathy, 13 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	24
Dann	Benign	0.34
DEOGEN2	Uncertain	0.79	D;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;.;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.9	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;D;D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0040	D;D;D;.;.
Sift4G	Benign	0.66	T;T;T;T;T
Polyphen		0.90	P;.;.;.;.
Vest4		0.54
MVP		0.80
MPC		1.8
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.48
gMVP		0.84

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: rs201458257; hg19: chr12-52188378;