Genetic Variant NM_006514.4:c.5137A>T (chr3-38698083-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006514.4(SCN10A):c.5137A>T(p.Met1713Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1713V) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.18

Publications

30 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
episodic pain syndrome, familial, 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SCN10A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41059425).

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
SCN10A	NM_006514.4	MANE Select	c.5137A>T	p.Met1713Leu	missense	Exon 28 of 28	NP_006505.4
SCN10A	NM_001293306.2		c.5134A>T	p.Met1712Leu	missense	Exon 27 of 27	NP_001280235.2
SCN10A	NM_001293307.2		c.4843A>T	p.Met1615Leu	missense	Exon 26 of 26	NP_001280236.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.5137A>T	p.Met1713Leu	missense	Exon 28 of 28	ENSP00000390600.2
SCN10A	ENST00000643924.1		c.5134A>T	p.Met1712Leu	missense	Exon 27 of 27	ENSP00000495595.1
SCN10A	ENST00000655275.1		c.5161A>T	p.Met1721Leu	missense	Exon 28 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

103772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.030

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.41

MetaSVM

Uncertain

0.070

MutationAssessor

Benign

-0.21

PhyloP100

6.2

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.0

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.036

Polyphen

0.0010

Vest4

0.24

MutPred

0.57

Gain of catalytic residue at M1713 (P = 0.0175)

MVP

0.67

MPC

0.056

ClinPred

0.90

GERP RS

5.4

Varity_R

0.47

gMVP

0.71

Mutation Taster

=88/12

polymorphism

(source)

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

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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