chr3-38550362-A-G

Variant names:

• chr3-38550362-A-G
• rs41311117
• NM_001099404.2:c.6010T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198056.3(SCN5A):​c.6010T>C​(p.Phe2004Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,534,052 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. F2004S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: SCN5A NM_198056.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:20 O:1
• Conservation: PhyloP100: 0.0740
• Publications: 49 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005137861).
• BP6: Variant 3-38550362-A-G is Benign according to our data. Variant chr3-38550362-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48315.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (322/148514) while in subpopulation NFE AF = 0.00384 (256/66638). AF 95% confidence interval is 0.00346. There are 0 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198056.3. 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.6010T>C	p.Phe2004Leu	missense	Exon 28 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.6007T>C	p.Phe2003Leu	missense	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.6010T>C	p.Phe2004Leu	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.6010T>C	p.Phe2004Leu	missense	Exon 28 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.6007T>C	p.Phe2003Leu	missense	Exon 28 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.6010T>C	p.Phe2004Leu	missense	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 321 AN: 148396 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00100

Gnomad ASJ AF: 0.00410

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.000995

GnomAD2 exomes AF: 0.00198 AC: 389 AN: 195994 AF XY: 0.00208

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000949

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000888

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00366 AC: 5071 AN: 1385538 Hom.: 13 Cov.: 31 AF XY: 0.00371 AC XY: 2520 AN XY: 678810

African (AFR) AF: 0.000284 AC: 9 AN: 31652

American (AMR) AF: 0.00106 AC: 39 AN: 36654

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 74 AN: 21192

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38898

South Asian (SAS) AF: 0.00100 AC: 74 AN: 73800

European-Finnish (FIN) AF: 0.000989 AC: 50 AN: 50576

Middle Eastern (MID) AF: 0.000801 AC: 4 AN: 4996

European-Non Finnish (NFE) AF: 0.00429 AC: 4597 AN: 1070794

Other (OTH) AF: 0.00390 AC: 222 AN: 56976

GnomAD4 genome AF: 0.00217 AC: 322 AN: 148514 Hom.: 0 Cov.: 33 AF XY: 0.00191 AC XY: 139 AN XY: 72592

African (AFR) AF: 0.000398 AC: 16 AN: 40220

American (AMR) AF: 0.000999 AC: 15 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 14 AN: 3412

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4920

South Asian (SAS) AF: 0.00151 AC: 7 AN: 4650

European-Finnish (FIN) AF: 0.00105 AC: 11 AN: 10460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00384 AC: 256 AN: 66638

Other (OTH) AF: 0.000983 AC: 2 AN: 2034

Alfa AF: 0.00263 Hom.: 3

Bravo AF: 0.00227

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000497 AC: 2

ESP6500EA AF: 0.00311 AC: 26

ExAC AF: 0.00190 AC: 227

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (10)
-	-	4	not specified (4)
-	2	-	Brugada syndrome 1 (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1E (1)
-	1	-	Long QT syndrome 3 (1)
-	-	1	Long QT syndrome 3;C4551804:Brugada syndrome 1 (1)
-	-	1	Long QT syndrome;C1142166:Brugada syndrome (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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	6.2
DANN	Benign	0.76
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.074
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.77		Loss of glycosylation at S2007 (P = 0.1612)
MVP		0.55
MPC		0.60
ClinPred		0.0016	T
GERP RS		-1.6
Varity_R		0.056
gMVP		0.36
Mutation Taster		=30/70	disease causing

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: rs41311117; hg19: chr3-38591853; COSMIC: COSV99048691; COSMIC: COSV99048691;