3-38725269-G-T

Variant names:

• chr3-38725269-G-T
• rs73062575
• NM_006514.4:c.3133C>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.3133C>A​(p.Pro1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,600,220 control chromosomes in the GnomAD database, including 653 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. P1045L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 33)
  • Exomes 𝑓: 0.026 (628 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0450
• Publications: 16 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=0.003993094).
• BP6: Variant 3-38725269-G-T is Benign according to our data. Variant chr3-38725269-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2636/152326) while in subpopulation NFE AF = 0.0285 (1940/68036). AF 95% confidence interval is 0.0275. There are 25 homozygotes in GnomAd4. There are 1160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2636 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.3133C>A	p.Pro1045Thr	missense	Exon 18 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.3130C>A	p.Pro1044Thr	missense	Exon 17 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.2839C>A	p.Pro947Thr	missense	Exon 16 of 26	NP_001280236.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.3133C>A	p.Pro1045Thr	missense	Exon 18 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.3130C>A	p.Pro1044Thr	missense	Exon 17 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.3157C>A	p.Pro1053Thr	missense	Exon 18 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2635 AN: 152208 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0155 AC: 3853 AN: 248330 AF XY: 0.0153

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00801

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0259 AC: 37530 AN: 1447894 Hom.: 628 Cov.: 33 AF XY: 0.0253 AC XY: 18168 AN XY: 719370

African (AFR) AF: 0.00340 AC: 113 AN: 33282

American (AMR) AF: 0.00752 AC: 333 AN: 44282

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 566 AN: 25876

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.00402 AC: 340 AN: 84550

European-Finnish (FIN) AF: 0.0146 AC: 774 AN: 53174

Middle Eastern (MID) AF: 0.00246 AC: 14 AN: 5692

European-Non Finnish (NFE) AF: 0.0309 AC: 34006 AN: 1101894

Other (OTH) AF: 0.0232 AC: 1383 AN: 59668

GnomAD4 genome AF: 0.0173 AC: 2636 AN: 152326 Hom.: 25 Cov.: 33 AF XY: 0.0156 AC XY: 1160 AN XY: 74490

African (AFR) AF: 0.00522 AC: 217 AN: 41570

American (AMR) AF: 0.0144 AC: 220 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

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

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1940 AN: 68036

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0229 Hom.: 164

Bravo AF: 0.0167

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0317 AC: 273

ExAC AF: 0.0147 AC: 1785

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.045
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Benign	0.33	T
Polyphen		0.10	B
Vest4		0.080
MPC		0.069
ClinPred		0.0014	T
GERP RS		2.5
Varity_R		0.053
gMVP		0.27
Mutation Taster		=94/6	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: rs73062575; hg19: chr3-38766760; COSMIC: COSV99081710;