rs555793953

chr12-51807428-AGAG-Achr12-51807428-AGAG-AGAGGAG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_014191.4(SCN8A):c.*3_*5del variant causes a stop retained, 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,604,900 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SCN8A NM_014191.4 stop_retained, 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.34

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 -17 ACMG points.

• BP6: Variant 12-51807428-AGAG-A is Benign according to our data. Variant chr12-51807428-AGAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 196030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51807428-AGAG-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00199 (303/152262) while in subpopulation AFR AF= 0.007 (291/41560). AF 95% confidence interval is 0.00634. There are 2 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	27/27	ENST00000627620.5
SCN8A	NM_014191.4	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	27/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	26/26
SCN8A	NM_001369788.1	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	27/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.*3_*5del		stop_retained_variant, 3_prime_UTR_variant	27/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152144 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000492 AC: 113 AN: 229728 Hom.: 0 AF XY: 0.000433 AC XY: 54 AN XY: 124836

Gnomad AFR exome AF: 0.00708

Gnomad AMR exome AF: 0.000462

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000201 AC: 292 AN: 1452638 Hom.: 1 AF XY: 0.000170 AC XY: 123 AN XY: 721718

Gnomad4 AFR exome AF: 0.00683

Gnomad4 AMR exome AF: 0.000532

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.000449

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152262 Hom.: 2 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74464

Gnomad4 AFR AF: 0.00700

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.00244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 25, 2014

- -

Early Infantile Epileptic Encephalopathy, Autosomal Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs555793953; hg19: chr12-52201212;