NM_001099404.2:c.6016C>G

Variant names:

• chr3-38550356-G-C
• rs45489199
• NM_001099404.2:c.6016C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001099404.2(SCN5A):​c.6016C>G​(p.Pro2006Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,534,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2006T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16 O:1
• Conservation: PhyloP100: -0.0910
• Publications: 46 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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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
• 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
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010572314).
• BP6: Variant 3-38550356-G-C is Benign according to our data. Variant chr3-38550356-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68024.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (159/149670) while in subpopulation NFE AF = 0.00182 (122/67028). AF 95% confidence interval is 0.00156. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. 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
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.6016C>G	p.Pro2006Ala	missense	Exon 28 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.6013C>G	p.Pro2005Ala	missense	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.6016C>G	p.Pro2006Ala	missense	Exon 28 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.6016C>G	p.Pro2006Ala	missense	Exon 28 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.6013C>G	p.Pro2005Ala	missense	Exon 28 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.6016C>G	p.Pro2006Ala	missense	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 159 AN: 149550 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00109 AC: 214 AN: 195458 AF XY: 0.00114

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.000411

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000881

GnomAD4 exome AF: 0.00125 AC: 1725 AN: 1385136 Hom.: 1 Cov.: 31 AF XY: 0.00122 AC XY: 826 AN XY: 678678

African (AFR) AF: 0.000127 AC: 4 AN: 31612

American (AMR) AF: 0.000247 AC: 9 AN: 36478

Ashkenazi Jewish (ASJ) AF: 0.000189 AC: 4 AN: 21142

East Asian (EAS) AF: 0.00 AC: 0 AN: 38902

South Asian (SAS) AF: 0.0000949 AC: 7 AN: 73740

European-Finnish (FIN) AF: 0.00125 AC: 63 AN: 50508

Middle Eastern (MID) AF: 0.00101 AC: 5 AN: 4932

European-Non Finnish (NFE) AF: 0.00148 AC: 1587 AN: 1070892

Other (OTH) AF: 0.000808 AC: 46 AN: 56930

GnomAD4 genome AF: 0.00106 AC: 159 AN: 149670 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 75 AN XY: 73196

African (AFR) AF: 0.000221 AC: 9 AN: 40668

American (AMR) AF: 0.000199 AC: 3 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4992

South Asian (SAS) AF: 0.00 AC: 0 AN: 4688

European-Finnish (FIN) AF: 0.00228 AC: 24 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00182 AC: 122 AN: 67028

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.00123 AC: 146

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	3	not specified (3)
-	1	1	Brugada syndrome 1 (2)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1E (1)
-	1	-	Long QT syndrome 3 (1)
-	-	1	Progressive familial heart block, type 1A (1)
-	-	1	SCN5A-related disorder (1)
-	-	1	Sick sinus syndrome 1 (1)
-	1	-	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	2.0
DANN	Benign	0.35
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.091
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.60	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.69
MPC		0.50
ClinPred		0.0037	T
GERP RS		-2.6
Varity_R		0.039
gMVP		0.43
Mutation Taster		=99/1	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: rs45489199; hg19: chr3-38591847;