rs764965507

Variant names:

• chr3-38750152-C-A
• rs764965507
• NM_006514.4:c.1788G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38750152-C-A
• chr3-38750152-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006514.4(SCN10A):​c.1788G>T​(p.Leu596Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.235
• 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):

• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27060816).
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.1788G>T	p.Leu596Phe	missense	Exon 13 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.1788G>T	p.Leu596Phe	missense	Exon 12 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.1494G>T	p.Leu498Phe	missense	Exon 11 of 26	NP_001280236.2	Q9Y5Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.1788G>T	p.Leu596Phe	missense	Exon 13 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.1788G>T	p.Leu596Phe	missense	Exon 12 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.1815G>T	p.Leu605Phe	missense	Exon 13 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250780 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000875

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: 0.00000548 AC: 8 AN: 1460744 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726700

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.0000672 AC: 3 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111286

Other (OTH) AF: 0.0000497 AC: 3 AN: 60354

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74372

African (AFR) AF: 0.0000724 AC: 3 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.0019
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.23
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.42
Sift	Benign	0.034	D
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.45
MutPred		0.29		Gain of glycosylation at Y600 (P = 0.0031)
MVP		0.89
MPC		0.34
ClinPred		0.82	D
GERP RS		0.41
Varity_R		0.11
gMVP		0.31
Mutation Taster		=78/22	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: rs764965507; hg19: chr3-38791643;