rs6599250

Variant names:

• chr3-38742538-T-C
• rs6599250
• NM_006514.4:c.1868-9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006514.4(SCN10A):​c.1868-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,609,664 control chromosomes in the GnomAD database, including 316,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38358 hom., cov: 32)
  • Exomes 𝑓: 0.61 (277776 hom.)
• Consequence: SCN10A NM_006514.4 intron
• Scores: Splicing: ADA: 0.00006857
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.669
• Publications: 22 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 (BayesDel_noAF=-0.79).
• BP6: Variant 3-38742538-T-C is Benign according to our data. Variant chr3-38742538-T-C is described in ClinVar as Benign. ClinVar VariationId is 259993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

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.1868-9A>G		intron	N/A	NP_006505.4
	SCN10A	NM_001293306.2		c.1868-9A>G		intron	N/A	NP_001280235.2
	SCN10A	NM_001293307.2		c.1574-9A>G		intron	N/A	NP_001280236.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.1868-9A>G		intron	N/A	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.1868-9A>G		intron	N/A	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.1895-9A>G		intron	N/A	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105735 AN: 151962 Hom.: 38285 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.649 AC: 161550 AN: 248812 AF XY: 0.641

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.860

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.615

GnomAD4 exome AF: 0.614 AC: 894283 AN: 1457584 Hom.: 277776 Cov.: 32 AF XY: 0.613 AC XY: 444436 AN XY: 725452

African (AFR) AF: 0.916 AC: 30636 AN: 33436

American (AMR) AF: 0.684 AC: 30579 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15685 AN: 26112

East Asian (EAS) AF: 0.858 AC: 34024 AN: 39674

South Asian (SAS) AF: 0.637 AC: 54914 AN: 86186

European-Finnish (FIN) AF: 0.542 AC: 28835 AN: 53200

Middle Eastern (MID) AF: 0.535 AC: 3078 AN: 5748

European-Non Finnish (NFE) AF: 0.594 AC: 658567 AN: 1108246

Other (OTH) AF: 0.630 AC: 37965 AN: 60266

GnomAD4 genome AF: 0.696 AC: 105874 AN: 152080 Hom.: 38358 Cov.: 32 AF XY: 0.694 AC XY: 51596 AN XY: 74332

African (AFR) AF: 0.907 AC: 37640 AN: 41518

American (AMR) AF: 0.670 AC: 10243 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2098 AN: 3462

East Asian (EAS) AF: 0.860 AC: 4444 AN: 5168

South Asian (SAS) AF: 0.661 AC: 3176 AN: 4808

European-Finnish (FIN) AF: 0.534 AC: 5641 AN: 10558

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40581 AN: 67952

Other (OTH) AF: 0.649 AC: 1372 AN: 2114

Alfa AF: 0.644 Hom.: 53933

Bravo AF: 0.715

Asia WGS AF: 0.769 AC: 2675 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Brugada syndrome (1)
-	-	1	Episodic pain syndrome, familial, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.71
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.010
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: rs6599250; hg19: chr3-38784029;