chr3-38698080-C-T

Variant names:

• chr3-38698080-C-T
• rs1553612991
• NM_006514.4:c.5140G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006514.4(SCN10A):​c.5140G>A​(p.Val1714Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1714D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.5140G>A	p.Val1714Ile	missense_variant	Exon 28 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.5140G>A	p.Val1714Ile	missense_variant	Exon 28 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.5137G>A	p.Val1713Ile	missense_variant	Exon 27 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.5164G>A	p.Val1722Ile	missense_variant	Exon 28 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Jun 02, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.3	L;.;L;.
PhyloP100		5.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.93	N;.;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D;.;.;.
Sift4G	Benign	0.50	T;.;.;.
Polyphen		0.61	P;.;P;.
Vest4		0.24
MutPred		0.58		Loss of glycosylation at S1709 (P = 0.1603);Loss of glycosylation at S1709 (P = 0.1603);Loss of glycosylation at S1709 (P = 0.1603);.;
MVP		0.76
MPC		0.22
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.29
gMVP		0.40
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1553612991; hg19: chr3-38739571;