Genetic Variant SCN10A:p.Thr1505Lys (chr3-38701982-G-T) – 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.4514C>A(p.Thr1505Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1505M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

Publications

4 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:

Genome browser will be placed here

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=0.34396452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4 link	c.4514C>A	p.Thr1505Lys	missense_variant	Exon 27 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN10A	ENST00000449082.3 link	c.4514C>A	p.Thr1505Lys	missense_variant	Exon 27 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1 link	c.4511C>A	p.Thr1504Lys	missense_variant	Exon 26 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1 link	c.4538C>A	p.Thr1513Lys	missense_variant	Exon 27 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251222

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.58

D;.;D;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.75

.;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

0.15

N;.;N;.

PhyloP100

3.5

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.8

D;.;.;.

REVEL

Uncertain

0.41

Sift

Benign

0.23

T;.;.;.

Sift4G

Benign

0.81

T;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.44

MutPred

0.42

Gain of methylation at T1505 (P = 0.0016);Gain of methylation at T1505 (P = 0.0016);Gain of methylation at T1505 (P = 0.0016);.;

MVP

0.96

MPC

0.099

ClinPred

0.68

GERP RS

4.7

Varity_R

0.46

gMVP

0.62

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over