chr3-38597924-AC-CG

Variant names:

• chr3-38597924-AC-CG
• NM_001099404.2:c.2066_2067delGTinsCG
• SCN5A p.Arg689Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000335.5(SCN5A):c.2066_2067delGTinsCG (p.Arg689Pro) variant causes a missense change. The gene SCN5A is a known oncogene (CancerMine: 1 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.R689H: Uncertain_significance (ClinVar VariationId 67710, 2 stars); p.R689P: Uncertain_significance (ClinVar VariationId 2435760, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 0 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000335.5. 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.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: NP_001092874.1 UniProt:
	SCN5A NM_000335.5	MANE Select	c.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: NP_000326.2
	SCN5A NM_198056.3		c.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: NP_932173.1 UniProt:

SCN5A NM_001099404.2

MANE Plus Clinical

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

missense

Prot: NP_001092874.1UniProt: H9KVD2

SCN5A NM_000335.5

MANE Select

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

missense

Prot: NP_000326.2

SCN5A NM_198056.3

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

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.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: ENSP00000410257.1 UniProt:
	SCN5A ENST00000423572.7	TSL:1MANE Select	c.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: ENSP00000398266.2 UniProt:
	SCN5A ENST00000333535.9	TSL:1	c.2066_2067delGTinsCG p.Arg689Pro	missense	N/A	Prot: ENSP00000328968.4 UniProt:

SCN5A ENST00000413689.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

missense

Prot: ENSP00000410257.1UniProt: H9KVD2

SCN5A ENST00000423572.7

TSL:1MANE Select

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

missense

Prot: ENSP00000398266.2UniProt: Q14524-2

SCN5A ENST00000333535.9

TSL:1

HGVSc / HGVSpc.2066_2067delGTinsCGp.Arg689Pro

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.18

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr3-38639415;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar