3-38597917-G-T

Variant names:

• chr3-38597917-G-T
• rs45553235
• NM_001099404.2:c.2074C>A
• SCN5A p.Gln692Lys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). BP6

The NM_000335.5(SCN5A):c.2074C>A (p.Gln692Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000236 (AC=381) in the gnomAD database across 1,613,936 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00069. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q692H: Uncertain_significance (ClinVar VariationId 940010, 1 star); p.Q692R: Uncertain_significance (ClinVar VariationId 4756306, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:15 O:1
• Conservation: PhyloP100: -0.0730
• Publications: 13 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: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: NP_001092874.1 UniProt:
	SCN5A NM_000335.5	MANE Select	c.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: NP_000326.2
	SCN5A NM_198056.3		c.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: NP_932173.1 UniProt:

SCN5A NM_001099404.2

MANE Plus Clinical

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

Exon rankExon 14 of 28

missense

Prot: NP_001092874.1UniProt: H9KVD2

SCN5A NM_000335.5

MANE Select

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

Exon rankExon 14 of 28

missense

Prot: NP_000326.2

SCN5A NM_198056.3

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

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.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: ENSP00000410257.1 UniProt:
	SCN5A ENST00000423572.7	TSL:1MANE Select	c.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: ENSP00000398266.2 UniProt:
	SCN5A ENST00000333535.9	TSL:1	c.2074C>A p.Gln692Lys	missense	Exon 14 of 28	Prot: ENSP00000328968.4 UniProt:

SCN5A ENST00000413689.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

Exon rankExon 14 of 28

missense

Prot: ENSP00000410257.1UniProt: H9KVD2

SCN5A ENST00000423572.7

TSL:1MANE Select

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

Exon rankExon 14 of 28

missense

Prot: ENSP00000398266.2UniProt: Q14524-2

SCN5A ENST00000333535.9

TSL:1

HGVSc / HGVSpc.2074C>Ap.Gln692Lys

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: 0.000230	AC:35	Hom:0	AN:152242	Cov:32
GnomAD2 exomes	AF: 0.000333	AC:83	Hom:	AN:248922	Cov:
GnomAD4 exome	AF: 0.000238	AC:348	Hom:0	AN:1461576	Cov:31
GnomAD4 genome	AF: 0.000217	AC:33	Hom:0	AN:152360	Cov:32
TOPMed (Bravo)	AF: 0.000264	AC:70	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000395	AC:46	Hom:0	AN:116434	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000157	AC:2	Hom:	AN:12756	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Turkish Variome	AF: 0.00521	AC:35	Hom:3	AN:6720	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.000104	3	28844
Epi25(Epilepsy)	0.000238	10	41954	0.000359	24	66888
SCHEMA(Schizophrenia)	0.000362	41	113140	0.000425	81	190602

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (6)
-	1	2	Long QT syndrome (3)
-	2	1	Long QT syndrome 3 (3)
-	1	2	not specified (3)
-	1	1	Brugada syndrome 1 (2)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1E (1)
-	1	-	Long QT syndrome 3;C4551804:Brugada syndrome 1 (1)
-	1	-	Progressive familial heart block, type 1A (1)
-	-	1	Sick sinus syndrome 1 (1)
-	1	-	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.9
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	15
CardioboostArm	Benign	0.00049
CardioboostCm	Benign	0.0014
DANN	Benign	0.94
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.68	D
GPN-Star LLR	N/A	-4.3
GPN-Star score	N/A	4.3
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.042	T
MetaSVM	Uncertain	0.062	D
Mutation Taster	N/A	41/59	disease causing
MutationAssessor	Benign	0.71	N
PhyloP100	Benign	-0.073
popEVE	Benign	-3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.065	T
Sift4G	Benign	0.68	T
Varity_R	N/A	0.081
VESM-3B	Benign	-5.7

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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.

1 normal (RUO)

1 assay found for this variant.

Research-use-only (RUO) calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

Scores from automatic patch clamping assay of SCN5A variants in HEK293T cells

Automatic patch clamping assay of SCN5A variants in HEK293T cells

• Gene: SCN5A
• Assay type: Direct protein function
• Mechanism: Sodium channel activity
• Model system: Immortalized human cells (Homo sapiens)
• Score: 98.5 · p.Gln692Lys (assay numbering)

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

BS3 strongFunctionally normalRUO ExCALIBR calibration: BS3 Strong (-4)

Other links and lift over

dbSNP: rs45553235;

hg19: chr3-38639408;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar