3-38723545-G-T

Variant names:

• chr3-38723545-G-T
• rs745921364
• NM_006514.4:c.3237C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006514.4(SCN10A):​c.3237C>A​(p.Asp1079Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,594,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. D1079N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.10
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13863128).
• BS2: High AC in GnomAdExome4 at 20 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.3237C>A	p.Asp1079Glu	missense	Exon 19 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.3234C>A	p.Asp1078Glu	missense	Exon 18 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.2943C>A	p.Asp981Glu	missense	Exon 17 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.3237C>A	p.Asp1079Glu	missense	Exon 19 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.3234C>A	p.Asp1078Glu	missense	Exon 18 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.3261C>A	p.Asp1087Glu	missense	Exon 19 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1441974 Hom.: 0 Cov.: 32 AF XY: 0.0000168 AC XY: 12 AN XY: 715794

African (AFR) AF: 0.0000303 AC: 1 AN: 33044

American (AMR) AF: 0.00 AC: 0 AN: 40980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 38726

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1101568

Other (OTH) AF: 0.0000168 AC: 1 AN: 59654

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.0010
DANN	Benign	0.86
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L
PhyloP100		-3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Benign	0.086	T
Sift4G	Benign	0.22	T
Polyphen		0.045	B
Vest4		0.079
MutPred		0.53		Gain of glycosylation at S1082 (P = 0.0122)
MVP		0.20
MPC		0.11
ClinPred		0.45	T
GERP RS		-9.6
Varity_R		0.068
gMVP		0.22
Mutation Taster		=97/3	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: rs745921364; hg19: chr3-38765036;