rs202192818

chr3-38771406-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_006514.4(SCN10A):c.472T>G(p.Tyr158Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000398 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y158Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: SCN10A NM_006514.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004975
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 5.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	5/28
SCN10A	ENST00000643924.1	c.472T>G	p.Tyr158Asp	missense_variant, splice_region_variant	4/27			A1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000470

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251360 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1461462 Hom.: 1 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000496

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74376

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000600

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated that p.(Y158D) generates a peak sodium current approximately two times larger than wild-type SCN10A channels, and when co-expressed with p.(R814H), the magnitude of the peak current was close to the sum of the average value of the peak currents of each variant expressed individually, such that both variants are reported to contribute to the electrical property of the channel (Savio-Galimberti et al., 2014); however, additional studies are needed to validate the functional effect of this variant in vivo; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25053638, 26733327, 28407228, 29396561, 34426522, 25691686, HolmstromL2022[Preprint]) -

Episodic pain syndrome, familial, 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 13, 2018	The p.Tyr158Asp has been reported on the same chromosome together with p. Arg814His, constituting a complex variant p.[Tyr158Asp, Arg814His] in several adult individuals with atrial fibrillation/polarization abnormality (Savio-Galimberti 2014, Jabbari 2015, Te Riele 2016). The Tyr158Asp and Arg814His variants were also identified in the study of patients with AV nodal reentrant tachycardia (Andreasen 2018). Savio-Galimberti et al. (2014) reported two families with possible variable penetrance and also showed that that these variants were associated with 2- and 4-fold increase in peak currents in a transient transfection and expression experiments in ND7/23 cells. Both Tyr158Asp and Arg814His variants are listed in gnomAD at population frequencies 0.04 and 0.05%, higher than expected for a pathogenic variant (Kobayashi 2017). Both variants are listed in ClinVar with current classification of uncertain significance (Variant ID 463260 and 420025). Thus, based on the available evidence, the complex variant p.[Tyr158Asp, Arg814His] was classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 02, 2021	- -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 14, 2021

- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 15, 2020

This sequence change replaces tyrosine with aspartic acid at codon 158 of the SCN10A protein (p.Tyr158Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs202192818, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with atrial fibrillation and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 25053638, 25085921, 26733327). All reported individuals also carried another change (c.2441G>A, p.Arg814His) that was shown to be in cis in at least three individuals (PMID: 25053638, 26733327). ClinVar contains an entry for this variant (Variation ID: 463260). Experimental studies in vitro have shown that this missense change generates a peak current that is 2 times larger than that of wild type (PMID: 25053638). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2019

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	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;M;.
MutationTaster	Benign	0.88	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.8	D;.;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.029	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.82
MVP		0.98
MPC		0.44
ClinPred		0.96	D
GERP RS		2.7
Varity_R		0.79
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs202192818; hg19: chr3-38812897; COSMIC: COSV101479466;