NM_001099404.2:c.2066G>A

Variant names:

• chr3-38597925-C-T
• rs199473145
• NM_001099404.2:c.2066G>A
• SCN5A p.Arg689His

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019).

The NM_001099404.2(SCN5A):c.2066G>A (p.Arg689His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000601 (AC=97) in the gnomAD database across 1,613,786 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00028. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R689C: Uncertain_significance (ClinVar VariationId 67709, 2 stars); p.R689P: Uncertain_significance (ClinVar VariationId 2435760, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11 O:1
• Conservation: PhyloP100: 0.183
• Publications: 29 publications found

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• SCN5A-related cardiac rhythm disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 28 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN5A NM_001099404.2	MANE Plus Clinical	c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: NP_001092874.1 UniProt:
	SCN5A NM_000335.5	MANE Select	c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: NP_000326.2
	SCN5A NM_198056.3		c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: NP_932173.1 UniProt:

SCN5A NM_001099404.2

MANE Plus Clinical

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: NP_001092874.1UniProt: H9KVD2

SCN5A NM_000335.5

MANE Select

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: NP_000326.2

SCN5A NM_198056.3

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: NP_932173.1UniProt: Q14524-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN5A ENST00000413689.6	TSL:5MANE Plus Clinical	c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: ENSP00000410257.1 UniProt:
	SCN5A ENST00000423572.7	TSL:1MANE Select	c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: ENSP00000398266.2 UniProt:
	SCN5A ENST00000333535.9	TSL:1	c.2066G>A p.Arg689His	missense	Exon 14 of 28	Prot: ENSP00000328968.4 UniProt:

SCN5A ENST00000413689.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: ENSP00000410257.1UniProt: H9KVD2

SCN5A ENST00000423572.7

TSL:1MANE Select

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: ENSP00000398266.2UniProt: Q14524-2

SCN5A ENST00000333535.9

TSL:1

HGVSc / HGVSpc.2066G>Ap.Arg689His

Exon rankExon 14 of 28

missense

Prot: ENSP00000328968.4UniProt: Q14524-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000985	AC:15	Hom:0	AN:152236	Cov:32
GnomAD2 exomes	AF: 0.0000924	AC:23	Hom:	AN:248792	Cov:
GnomAD4 exome	AF: 0.0000561	AC:82	Hom:0	AN:1461432	Cov:31
GnomAD4 genome	AF: 0.0000985	AC:15	Hom:0	AN:152354	Cov:32
TOPMed (Bravo)	AF: 0.0000756	AC:20	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000688	AC:19	Hom:0	AN:276346	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000784	AC:1	Hom:	AN:12748	Cov:
Korea4K (4,157 Koreans)	AF: 0.000691	AC:5	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000481	AC:59	Hom:0	AN:122762	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41948	0.000105	7	66886
SCHEMA(Schizophrenia)	0.000265	30	113094	0.000215	41	190532

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (4)
-	2	-	Cardiac arrhythmia (2)
-	2	-	Long QT syndrome (2)
-	1	-	Brugada syndrome 1 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)
-	1	-	SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.9
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	15
CardioboostArm	Benign	0.0000014
CardioboostCm	Benign	0.0092
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.11	N
FuncVEP CTI	Benign	0.00040
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.4
LIST_S2	Benign	0.27	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.023	D
Mutation Taster	N/A	46/54	disease causing
MutationAssessor	Benign	0.71	N
PhyloP100	Benign	0.18
popEVE	Benign	-3.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.58
Sift	Benign	0.15	T
Sift4G	Benign	0.083	T
Varity_R	N/A	0.037
VESM-3B	Benign	-5.8

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199473145;

hg19: chr3-38639416;

COSMIC: COSV61116129;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar