3-38760726-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006514.4(SCN10A):c.905G>A(p.Arg302Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R302R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: -1.73

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03218162).
• BP6: Variant 3-38760726-C-T is Benign according to our data. Variant chr3-38760726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376797.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr3-38760726-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.905G>A	p.Arg302Gln	missense_variant	8/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.905G>A	p.Arg302Gln	missense_variant	8/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.932G>A	p.Arg311Gln	missense_variant	8/28
SCN10A	ENST00000643924.1	c.905G>A	p.Arg302Gln	missense_variant	7/27			A1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251084 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135672

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.000380 AC XY: 276 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74454

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	A variant of uncertain significance has been identified in the SCN10A gene. The R302Q variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in other individuals referred for arrhythmia/cardiomyopathy genetic testing at GeneDx, although these individuals harbored additional cardiogenetic variants and no informative segregation data are available to further clarify the role of this variant in disease. The R302Q variant is also observed in 50/126324 (0.04%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Additionally, while R302Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

Episodic pain syndrome, familial, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Benign	0.93
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0053	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.73	N;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.14	T;.;.;.
Sift4G	Benign	0.24	T;.;.;.
Polyphen		0.0050	B;.;B;.
Vest4		0.051
MVP		0.35
MPC		0.068
ClinPred		0.022	T
GERP RS		-2.6
Varity_R		0.028
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs201955990; hg19: chr3-38802217; COSMIC: COSV99081709;