Genetic Variant SCN10A:p.Met1949Lys (chr3-38697374-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006514.4(SCN10A):c.5846T>A(p.Met1949Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1949T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00100

Publications

0 publications found

Variant links:

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):

sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
episodic pain syndrome, familial, 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SCN10A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039416224).

BP6

Variant 3-38697374-A-T is Benign according to our data. Variant chr3-38697374-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1750038.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN10A	NM_006514.4	MANE Select	c.5846T>A	p.Met1949Lys	missense	Exon 28 of 28	NP_006505.4	Q9Y5Y9
SCN10A	NM_001293306.2		c.5843T>A	p.Met1948Lys	missense	Exon 27 of 27	NP_001280235.2	Q9Y5Y9
SCN10A	NM_001293307.2		c.5552T>A	p.Met1851Lys	missense	Exon 26 of 26	NP_001280236.2	Q9Y5Y9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.5846T>A	p.Met1949Lys	missense	Exon 28 of 28	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1		c.5843T>A	p.Met1948Lys	missense	Exon 27 of 27	ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1		c.5870T>A	p.Met1957Lys	missense	Exon 28 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.032

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.053

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.040

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.26

M_CAP

Benign

0.031

MetaRNN

Benign

0.039

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.0

PhyloP100

0.0010

PrimateAI

Benign

0.31

PROVEAN

Benign

2.7

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

0.98

Polyphen

0.0

Vest4

0.088

MutPred

0.17

Gain of ubiquitination at M1949 (P = 0.0042)

MVP

0.23

MPC

0.089

ClinPred

0.059

GERP RS

0.84

Varity_R

0.085

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over