rs138832868

Variant names:

• chr3-38713959-C-T
• rs138832868
• NM_006514.4:c.3803G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006514.4(SCN10A):​c.3803G>A​(p.Arg1268Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,613,264 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R1268W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (11 hom.)
• Consequence: SCN10A NM_006514.4 missense, splice_region
• Scores: Splicing: ADA: 0.7424
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 7.89
• Publications: 26 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030475438).
• BP6: Variant 3-38713959-C-T is Benign according to our data. Variant chr3-38713959-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240673.
• BS2: High AC in GnomAd4 at 370 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.3803G>A	p.Arg1268Gln	missense splice_region	Exon 22 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.3800G>A	p.Arg1267Gln	missense splice_region	Exon 21 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.3509G>A	p.Arg1170Gln	missense splice_region	Exon 20 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.3803G>A	p.Arg1268Gln	missense splice_region	Exon 22 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.3800G>A	p.Arg1267Gln	missense splice_region	Exon 21 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.3827G>A	p.Arg1276Gln	missense splice_region	Exon 22 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00166 AC: 416 AN: 251046 AF XY: 0.00173

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00288

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00252 AC: 3678 AN: 1460986 Hom.: 11 Cov.: 30 AF XY: 0.00242 AC XY: 1757 AN XY: 726776

African (AFR) AF: 0.000269 AC: 9 AN: 33454

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86218

European-Finnish (FIN) AF: 0.00244 AC: 130 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5118

European-Non Finnish (NFE) AF: 0.00306 AC: 3406 AN: 1111976

Other (OTH) AF: 0.00136 AC: 82 AN: 60320

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74460

African (AFR) AF: 0.000433 AC: 18 AN: 41562

American (AMR) AF: 0.00190 AC: 29 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00277 Hom.: 3

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00175 AC: 213

EpiCase AF: 0.00240

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.030	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.086	B
Vest4		0.92
MVP		0.92
MPC		0.11
ClinPred		0.062	T
GERP RS		4.1
Varity_R		0.72
gMVP		0.81
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.63
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: rs138832868; hg19: chr3-38755450; COSMIC: COSV99081711;