12-51622393-T-C

Variant names:

• chr12-51622393-T-C
• rs7300982
• NM_001330260.2:c.-55+31034T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014191.4(SCN8A):​c.-55+31034T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 152,222 control chromosomes in the GnomAD database, including 58,644 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (58644 hom., cov: 31)
• Consequence: SCN8A NM_014191.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 5 publications found

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]

SCN8A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014191.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.-55+31034T>C		intron	N/A	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.-55+31034T>C		intron	N/A	NP_055006.1
	SCN8A	NM_001177984.3		c.-55+31034T>C		intron	N/A	NP_001171455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.-55+31034T>C		intron	N/A	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.-55+31034T>C		intron	N/A	ENSP00000487583.2
	SCN8A	ENST00000546961.1	TSL:1	c.-55+31720T>C		intron	N/A	ENSP00000486828.1

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133244 AN: 152100 Hom.: 58587 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.877

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.876 AC: 133362 AN: 152222 Hom.: 58644 Cov.: 31 AF XY: 0.877 AC XY: 65241 AN XY: 74422

African (AFR) AF: 0.820 AC: 34037 AN: 41520

American (AMR) AF: 0.907 AC: 13875 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2763 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5143 AN: 5180

South Asian (SAS) AF: 0.772 AC: 3724 AN: 4822

European-Finnish (FIN) AF: 0.938 AC: 9952 AN: 10608

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.895 AC: 60902 AN: 68012

Other (OTH) AF: 0.878 AC: 1856 AN: 2114

Alfa AF: 0.883 Hom.: 101544

Bravo AF: 0.875

Asia WGS AF: 0.896 AC: 3114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.5
DANN	Benign	0.58
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7300982; hg19: chr12-52016177;