rs750073618

Variant names:

• chr3-38792132-G-A
• rs750073618
• NM_006514.4:c.307C>T
• SCN10A p.Arg103Trp

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingPP3BS2

The NM_006514.4(SCN10A):c.307C>T (p.Arg103Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000254 (AC=41) in the gnomAD database across 1,613,706 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000022. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R103Q: Likely_benign (ClinVar VariationId 532134, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.834
• Publications: 1 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: PanelApp Australia, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• 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, G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000022 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 41 (pure AD gene, not AR).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.307C>T	p.Arg103Trp	missense	Exon 3 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.307C>T	p.Arg103Trp	missense	Exon 2 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.307C>T	p.Arg103Trp	missense	Exon 2 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.307C>T	p.Arg103Trp	missense	Exon 3 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.307C>T	p.Arg103Trp	missense	Exon 2 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.307C>T	p.Arg103Trp	missense	Exon 3 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152106	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:250980	Cov:
GnomAD4 exome	AF: 0.0000260	AC:38	Hom:0	AN:1461600	Cov:31
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152106	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	9620	0.0000960 *	1	10422
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28406	0.0000694	2	28824
Epi25(Epilepsy)	0.00	0	41948	0.0000748	5	66860
SCHEMA(Schizophrenia)	0.00000885	1	113032	0.0000158	3	190456

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	42/58	disease causing
MutationAssessor	Pathogenic	3.3	M
PhyloP100	Benign	0.83
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.80
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.12	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs750073618;

hg19: chr3-38833623;

COSMIC: COSV71860493;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar