rs555793953

Variant names:

• chr12-51807428-AGAG-A
• rs555793953
• NM_001330260.2:c.*3_*5delGAG

Your query was ambiguous. Multiple possible variants found:

• chr12-51807428-AGAG-A
• chr12-51807428-AGAG-AGAGGAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001330260.2(SCN8A):​c.*3_*5delGAG variant causes a 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_001330260.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.34
• 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 -16 ACMG points.

• BP6: Variant 12-51807428-AGAG-A is Benign according to our data. Variant chr12-51807428-AGAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 303 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.*3_*5delGAG		3_prime_UTR	Exon 27 of 27	NP_001317189.1
	SCN8A	NM_014191.4	MANE Plus Clinical	c.*3_*5delGAG		3_prime_UTR	Exon 27 of 27	NP_055006.1
	SCN8A	NM_001177984.3		c.*3_*5delGAG		3_prime_UTR	Exon 26 of 26	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.*3_*5delGAG		3_prime_UTR	Exon 27 of 27	ENSP00000346534.4
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.*3_*5delGAG		3_prime_UTR	Exon 27 of 27	ENSP00000487583.2
	SCN8A	ENST00000662684.1		c.*3_*5delGAG		3_prime_UTR	Exon 27 of 27	ENSP00000499636.1

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

GnomAD2 exomes AF: 0.000492 AC: 113 AN: 229728 AF XY: 0.000433

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 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

African (AFR) AF: 0.00683 AC: 227 AN: 33232

American (AMR) AF: 0.000532 AC: 23 AN: 43198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 85026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107184

Other (OTH) AF: 0.000449 AC: 27 AN: 60106

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

African (AFR) AF: 0.00700 AC: 291 AN: 41560

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.00244

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Early Infantile Epileptic Encephalopathy, Autosomal Dominant (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=99/1	polymorphism

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: rs555793953; hg19: chr12-52201212;