NM_006514.4:c.5089G>A

Variant names:

• chr3-38698131-C-T
• rs77804526
• NM_006514.4:c.5089G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006514.4(SCN10A):​c.5089G>A​(p.Val1697Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,082 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1697A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 31)
  • Exomes 𝑓: 0.013 (170 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.352
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009874433).
• BP6: Variant 3-38698131-C-T is Benign according to our data. Variant chr3-38698131-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00899 (1368/152218) while in subpopulation SAS AF = 0.022 (106/4810). AF 95% confidence interval is 0.0186. There are 8 homozygotes in GnomAd4. There are 665 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1368 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.5089G>A	p.Val1697Ile	missense	Exon 28 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.5086G>A	p.Val1696Ile	missense	Exon 27 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.4795G>A	p.Val1599Ile	missense	Exon 26 of 26	NP_001280236.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.5089G>A	p.Val1697Ile	missense	Exon 28 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.5086G>A	p.Val1696Ile	missense	Exon 27 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.5113G>A	p.Val1705Ile	missense	Exon 28 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1365 AN: 152100 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0117 AC: 2930 AN: 251324 AF XY: 0.0130

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00480

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0129 AC: 18887 AN: 1461864 Hom.: 170 Cov.: 91 AF XY: 0.0135 AC XY: 9809 AN XY: 727232

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.00570 AC: 255 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 512 AN: 26136

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39698

South Asian (SAS) AF: 0.0260 AC: 2245 AN: 86258

European-Finnish (FIN) AF: 0.00534 AC: 285 AN: 53420

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14609 AN: 1111990

Other (OTH) AF: 0.0123 AC: 744 AN: 60390

GnomAD4 genome AF: 0.00899 AC: 1368 AN: 152218 Hom.: 8 Cov.: 31 AF XY: 0.00894 AC XY: 665 AN XY: 74420

African (AFR) AF: 0.00303 AC: 126 AN: 41562

American (AMR) AF: 0.00720 AC: 110 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4810

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10600

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 892 AN: 68006

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0115 Hom.: 38

Bravo AF: 0.00855

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0123 AC: 1496

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0162

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.70
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.24
Sift	Benign	0.24	T
Sift4G	Benign	0.68	T
Polyphen		0.024	B
Vest4		0.037
MPC		0.052
ClinPred		0.00089	T
GERP RS		0.24
Varity_R		0.060
gMVP		0.56
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: rs77804526; hg19: chr3-38739622;