chr3-38752306-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006514.4(SCN10A):c.1668A>C(p.Gln556His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q556L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.125

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
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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14888412).

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.1668A>C	p.Gln556His	missense	Exon 12 of 28	NP_006505.4
SCN10A	NM_001293306.2		c.1668A>C	p.Gln556His	missense	Exon 11 of 27	NP_001280235.2
SCN10A	NM_001293307.2		c.1462-2122A>C		intron	N/A	NP_001280236.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.1668A>C	p.Gln556His	missense	Exon 12 of 28	ENSP00000390600.2
SCN10A	ENST00000643924.1		c.1668A>C	p.Gln556His	missense	Exon 11 of 27	ENSP00000495595.1
SCN10A	ENST00000655275.1		c.1695A>C	p.Gln565His	missense	Exon 12 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457562

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725046

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33272

American (AMR)

AF:

0.00

AC:

AN:

44238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.00

AC:

AN:

85510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109954

Other (OTH)

AF:

0.0000166

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.0040

BayesDel_noAF

Benign

-0.24

CADD

Benign

9.0

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.039

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.25

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.054

MutationAssessor

Benign

1.6

PhyloP100

-0.13

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.22

REVEL

Uncertain

0.29

Sift

Benign

0.24

Sift4G

Benign

0.20

Polyphen

0.97

Vest4

0.27

MutPred

0.26

Loss of glycosylation at P553 (P = 0.0103)

MVP

0.65

MPC

0.16

ClinPred

0.43

GERP RS

-0.30

Varity_R

0.047

gMVP

0.33

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over