rs74717885

Variant names:

• chr3-38763578-T-C
• rs74717885
• NM_006514.4:c.618A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006514.4(SCN10A):​c.618A>G​(p.Ile206Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,802 control chromosomes in the GnomAD database, including 716 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I206V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (73 hom., cov: 32)
  • Exomes 𝑓: 0.019 (643 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.537
• Publications: 12 publications found

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SCN10A Gene-Disease associations (from GenCC):

• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• sodium channelopathy-related small fiber neuropathy

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

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017729998).
• BP6: Variant 3-38763578-T-C is Benign according to our data. Variant chr3-38763578-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006514.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.618A>G	p.Ile206Met	missense	Exon 6 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.618A>G	p.Ile206Met	missense	Exon 5 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.618A>G	p.Ile206Met	missense	Exon 5 of 26	NP_001280236.2	Q9Y5Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.618A>G	p.Ile206Met	missense	Exon 6 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.618A>G	p.Ile206Met	missense	Exon 5 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.618A>G	p.Ile206Met	missense	Exon 6 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2437 AN: 152220 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0255 AC: 6413 AN: 251314 AF XY: 0.0267

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.00648

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0192 AC: 28084 AN: 1461466 Hom.: 643 Cov.: 30 AF XY: 0.0200 AC XY: 14515 AN XY: 727070

African (AFR) AF: 0.00245 AC: 82 AN: 33474

American (AMR) AF: 0.00747 AC: 334 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 545 AN: 26134

East Asian (EAS) AF: 0.134 AC: 5304 AN: 39696

South Asian (SAS) AF: 0.0385 AC: 3319 AN: 86236

European-Finnish (FIN) AF: 0.00691 AC: 369 AN: 53378

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5766

European-Non Finnish (NFE) AF: 0.0150 AC: 16651 AN: 1111688

Other (OTH) AF: 0.0222 AC: 1338 AN: 60376

GnomAD4 genome AF: 0.0160 AC: 2436 AN: 152336 Hom.: 73 Cov.: 32 AF XY: 0.0175 AC XY: 1305 AN XY: 74494

African (AFR) AF: 0.00303 AC: 126 AN: 41572

American (AMR) AF: 0.0104 AC: 159 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.146 AC: 755 AN: 5188

South Asian (SAS) AF: 0.0383 AC: 185 AN: 4824

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10626

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0152 AC: 1037 AN: 68034

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0186 Hom.: 148

Bravo AF: 0.0159

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0256 AC: 3106

Asia WGS AF: 0.0660 AC: 228 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0192

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.54
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Benign	0.20	T
Polyphen		0.0080	B
Vest4		0.077
MPC		0.066
ClinPred		0.0079	T
GERP RS		-0.84
Varity_R		0.14
gMVP		0.47
Mutation Taster		=93/7	polymorphism (auto)

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: rs74717885; hg19: chr3-38805069; COSMIC: COSV71860737;