rs60637

Variant names:

• chr12-51806958-C-A
• rs60637
• NM_001330260.2:c.5472C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51806958-C-A
• chr12-51806958-C-G
• chr12-51806958-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001330260.2(SCN8A):​c.5472C>A​(p.Pro1824Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,622 control chromosomes in the GnomAD database, including 406,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1824P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.60 (30605 hom., cov: 32)
  • Exomes 𝑓: 0.71 (376227 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0570
• Publications: 25 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-51806958-C-A is Benign according to our data. Variant chr12-51806958-C-A is described in ClinVar as Benign. ClinVar VariationId is 130251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.057 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.5472C>A	p.Pro1824Pro	synonymous_variant	Exon 27 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.5472C>A	p.Pro1824Pro	synonymous_variant	Exon 27 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.5349C>A	p.Pro1783Pro	synonymous_variant	Exon 26 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.5349C>A	p.Pro1783Pro	synonymous_variant	Exon 26 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.5472C>A	p.Pro1824Pro	synonymous_variant	Exon 27 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.5472C>A	p.Pro1824Pro	synonymous_variant	Exon 27 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.5505C>A	p.Pro1835Pro	synonymous_variant	Exon 26 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.5349C>A	p.Pro1783Pro	synonymous_variant	Exon 25 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91608 AN: 151874 Hom.: 30597 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.816

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.654 AC: 163303 AN: 249530 AF XY: 0.647

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.574

Gnomad FIN exome AF: 0.720

Gnomad NFE exome AF: 0.751

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.707 AC: 1033975 AN: 1461630 Hom.: 376227 Cov.: 64 AF XY: 0.699 AC XY: 507872 AN XY: 727082

African (AFR) AF: 0.291 AC: 9744 AN: 33480

American (AMR) AF: 0.743 AC: 33235 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17725 AN: 26132

East Asian (EAS) AF: 0.529 AC: 20990 AN: 39698

South Asian (SAS) AF: 0.370 AC: 31910 AN: 86254

European-Finnish (FIN) AF: 0.733 AC: 39134 AN: 53394

Middle Eastern (MID) AF: 0.619 AC: 3568 AN: 5768

European-Non Finnish (NFE) AF: 0.752 AC: 836321 AN: 1111808

Other (OTH) AF: 0.685 AC: 41348 AN: 60374

GnomAD4 genome AF: 0.603 AC: 91631 AN: 151992 Hom.: 30605 Cov.: 32 AF XY: 0.598 AC XY: 44391 AN XY: 74270

African (AFR) AF: 0.308 AC: 12746 AN: 41446

American (AMR) AF: 0.707 AC: 10807 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2277 AN: 3468

East Asian (EAS) AF: 0.572 AC: 2948 AN: 5150

South Asian (SAS) AF: 0.367 AC: 1767 AN: 4820

European-Finnish (FIN) AF: 0.705 AC: 7420 AN: 10520

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51376 AN: 67994

Other (OTH) AF: 0.649 AC: 1370 AN: 2110

Alfa AF: 0.692 Hom.: 65315

Bravo AF: 0.598

Asia WGS AF: 0.439 AC: 1526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 82. Only high quality variants are reported. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cognitive impairment with or without cerebellar ataxia Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizures, benign familial infantile, 5 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myoclonus, familial, 2 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 13 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.4
DANN	Benign	0.85
PhyloP100		-0.057
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs60637; hg19: chr12-52200742; COSMIC: COSV61977088; COSMIC: COSV61977088;