rs35242963

chr12-51721743-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014191.4(SCN8A):c.1833G>T(p.Arg611=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,607,236 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: SCN8A NM_014191.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.231

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-51721743-G-T is Benign according to our data. Variant chr12-51721743-G-T is described in ClinVar as [Benign]. Clinvar id is 130242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51721743-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1990/152280) while in subpopulation AFR AF= 0.0458 (1905/41560). AF 95% confidence interval is 0.0441. There are 34 homozygotes in gnomad4. There are 943 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1988 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1833G>T	p.Arg611=	synonymous_variant	12/27	ENST00000627620.5
SCN8A	NM_014191.4	c.1833G>T	p.Arg611=	synonymous_variant	12/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.1833G>T	p.Arg611=	synonymous_variant	12/26
SCN8A	NM_001369788.1	c.1833G>T	p.Arg611=	synonymous_variant	12/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1833G>T	p.Arg611=	synonymous_variant	12/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1833G>T	p.Arg611=	synonymous_variant	12/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1988 AN: 152162 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00319 AC: 727 AN: 228070 Hom.: 17 AF XY: 0.00236 AC XY: 295 AN XY: 125198

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00143 AC: 2084 AN: 1454956 Hom.: 47 Cov.: 31 AF XY: 0.00122 AC XY: 879 AN XY: 723368

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00261

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000748

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.0131 AC: 1990 AN: 152280 Hom.: 34 Cov.: 31 AF XY: 0.0127 AC XY: 943 AN XY: 74462

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00380 Hom.: 5

Bravo AF: 0.0152

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Cognitive impairment with or without cerebellar ataxia;C3281191:Developmental and epileptic encephalopathy, 13;C4310728:Seizures, benign familial infantile, 5;C5193056:Myoclonus, familial, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Benign	0.89

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: rs35242963; hg19: chr12-52115527;