rs765240974

Variant names:

• chr12-51745899-A-G
• rs765240974
• NM_001330260.2:c.1999-4A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-51745899-A-G
• chr12-51745899-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001330260.2(SCN8A):​c.1999-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000952 in 1,261,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Scores: Splicing: ADA: 0.00006585
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.599
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-51745899-A-G is Benign according to our data. Variant chr12-51745899-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1091429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.1999-4A>G		splice_region intron	N/A	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.1999-4A>G		splice_region intron	N/A	NP_055006.1
	SCN8A	NM_001177984.3		c.1999-4A>G		splice_region intron	N/A	NP_001171455.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.1999-4A>G		splice_region intron	N/A	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1999-4A>G		splice_region intron	N/A	ENSP00000487583.2
	SCN8A	ENST00000599343.5	TSL:5	c.2032-4A>G		splice_region intron	N/A	ENSP00000476447.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000952 AC: 12 AN: 1261076 Hom.: 0 Cov.: 33 AF XY: 0.00000806 AC XY: 5 AN XY: 620466

African (AFR) AF: 0.00 AC: 0 AN: 27156

American (AMR) AF: 0.00 AC: 0 AN: 25430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19724

East Asian (EAS) AF: 0.00 AC: 0 AN: 33918

South Asian (SAS) AF: 0.00 AC: 0 AN: 61404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4996

European-Non Finnish (NFE) AF: 0.0000121 AC: 12 AN: 993860

Other (OTH) AF: 0.00 AC: 0 AN: 51154

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.81
DANN	Benign	0.53
PhyloP100		-0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs765240974; hg19: chr12-52139683;