rs35332705

Variant names:

• chr3-38750172-C-T
• rs35332705
• NM_006514.4:c.1768G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006514.4(SCN10A):​c.1768G>A​(p.Gly590Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,609,618 control chromosomes in the GnomAD database, including 6 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.78
• Publications: 2 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):

• sodium channelopathy-related small fiber neuropathy

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

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062061846).
• BP6: Variant 3-38750172-C-T is Benign according to our data. Variant chr3-38750172-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 530 AD,Unknown gene.

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.1768G>A	p.Gly590Arg	missense	Exon 13 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.1768G>A	p.Gly590Arg	missense	Exon 12 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.1474G>A	p.Gly492Arg	missense	Exon 11 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.1768G>A	p.Gly590Arg	missense	Exon 13 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.1768G>A	p.Gly590Arg	missense	Exon 12 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.1795G>A	p.Gly599Arg	missense	Exon 13 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152224 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00103 AC: 257 AN: 250256 AF XY: 0.000902

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000303 AC: 441 AN: 1457276 Hom.: 2 Cov.: 29 AF XY: 0.000284 AC XY: 206 AN XY: 725242

African (AFR) AF: 0.00961 AC: 321 AN: 33390

American (AMR) AF: 0.00141 AC: 63 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1108304

Other (OTH) AF: 0.000697 AC: 42 AN: 60236

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152342 Hom.: 4 Cov.: 33 AF XY: 0.00361 AC XY: 269 AN XY: 74504

African (AFR) AF: 0.0119 AC: 496 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00386

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Episodic pain syndrome, familial, 2 (1)
-	-	1	SCN10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.35
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	-0.85	N
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.24
Sift	Benign	0.81	T
Sift4G	Benign	0.38	T
Polyphen		0.73	P
Vest4		0.38
MutPred		0.24		Gain of solvent accessibility (P = 0.0037)
MVP		0.64
MPC		0.14
ClinPred		0.043	T
GERP RS		3.6
Varity_R		0.044
gMVP		0.43
Mutation Taster		=96/4	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: rs35332705; hg19: chr3-38791663;