rs138404783

chr3-38752313-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006514.4(SCN10A):c.1661T>C(p.Leu554Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,610,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L554I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 0.518

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14423016).
• BP6: Variant 3-38752313-A-G is Benign according to our data. Variant chr3-38752313-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr3-38752313-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.1661T>C	p.Leu554Pro	missense_variant	12/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.1661T>C	p.Leu554Pro	missense_variant	12/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.1688T>C	p.Leu563Pro	missense_variant	12/28
SCN10A	ENST00000643924.1	c.1661T>C	p.Leu554Pro	missense_variant	11/27			A1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000928 AC: 23 AN: 247808 Hom.: 0 AF XY: 0.0000970 AC XY: 13 AN XY: 133970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 81 AN: 1458858 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39 AN XY: 725694

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74384

Gnomad4 AFR AF: 0.00

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	This variant is associated with the following publications: (PMID: 23115331, 24006052, 24820863, 23986244, 25060923, 24763188) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2016	- -

Episodic pain syndrome, familial, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 20, 2012

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 28, 2022

Variant summary: SCN10A c.1661T>C (p.Leu554Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 247808 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SCN10A causing SCN10A-Related Disorders, allowing no conclusion about variant significance. c.1661T>C has been reported in the literature in individuals affected with SCN10A-Related Disorders. This report does not provide unequivocal conclusions about association of the variant with SCN10A-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function and showed L554 affected sodium channel function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=2, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 554 of the SCN10A protein (p.Leu554Pro). This variant is present in population databases (rs138404783, gnomAD 0.02%). This missense change has been observed in individual(s) with neuropathy (PMID: 23115331). ClinVar contains an entry for this variant (Variation ID: 89014). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN10A protein function. Experimental studies have shown that this missense change affects SCN10A function (PMID: 23115331). 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

Jun 24, 2021

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	0.068
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.056	N
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M;.;M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.44	N;.;.;.
REVEL	Uncertain	0.59
Sift	Benign	0.24	T;.;.;.
Sift4G	Benign	0.22	T;.;.;.
Polyphen		0.93	P;.;P;.
Vest4		0.72
MVP		0.71
MPC		0.25
ClinPred		0.094	T
GERP RS		0.99
Varity_R		0.15
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138404783; hg19: chr3-38793804;