12-51765796-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014191.4(SCN8A):c.2670C>T(p.Ala890=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,962 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). Synonymous variant affecting the same amino acid position (i.e. A890A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SCN8A NM_014191.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.879

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-51765796-C-T is Benign according to our data. Variant chr12-51765796-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260351.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}. Variant chr12-51765796-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.879 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000309 (47/152146) while in subpopulation AFR AF= 0.00111 (46/41514). AF 95% confidence interval is 0.000853. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.2670C>T	p.Ala890=	synonymous_variant	16/27	ENST00000627620.5
SCN8A	NM_014191.4	c.2670C>T	p.Ala890=	synonymous_variant	16/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.2670C>T	p.Ala890=	synonymous_variant	16/26
SCN8A	NM_001369788.1	c.2670C>T	p.Ala890=	synonymous_variant	16/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.2670C>T	p.Ala890=	synonymous_variant	16/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.2670C>T	p.Ala890=	synonymous_variant	16/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250430 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135690

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727190

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74392

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2020

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

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	6.4
Dann	Benign	0.54

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: rs374452942; hg19: chr12-52159580;