3-38698354-A-G

Variant names:

• chr3-38698354-A-G
• rs6599242
• NM_006514.4:c.4866T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006514.4(SCN10A):​c.4866T>C​(p.Ser1622Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,614,070 control chromosomes in the GnomAD database, including 675,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66000 hom., cov: 30)
  • Exomes 𝑓: 0.91 (609773 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.831
• Publications: 23 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
• Brugada syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-38698354-A-G is Benign according to our data. Variant chr3-38698354-A-G is described in ClinVar as Benign. ClinVar VariationId is 95404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.831 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 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.4866T>C	p.Ser1622Ser	synonymous	Exon 28 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.4863T>C	p.Ser1621Ser	synonymous	Exon 27 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.4572T>C	p.Ser1524Ser	synonymous	Exon 26 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.4866T>C	p.Ser1622Ser	synonymous	Exon 28 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.4863T>C	p.Ser1621Ser	synonymous	Exon 27 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.4890T>C	p.Ser1630Ser	synonymous	Exon 28 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141560 AN: 152060 Hom.: 65940 Cov.: 30

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.932

GnomAD2 exomes AF: 0.920 AC: 231246 AN: 251356 AF XY: 0.917

Gnomad AFR exome AF: 0.961

Gnomad AMR exome AF: 0.914

Gnomad ASJ exome AF: 0.943

Gnomad EAS exome AF: 0.969

Gnomad FIN exome AF: 0.935

Gnomad NFE exome AF: 0.916

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.913 AC: 1334834 AN: 1461892 Hom.: 609773 Cov.: 83 AF XY: 0.912 AC XY: 663209 AN XY: 727246

African (AFR) AF: 0.962 AC: 32193 AN: 33480

American (AMR) AF: 0.916 AC: 40986 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.943 AC: 24658 AN: 26136

East Asian (EAS) AF: 0.963 AC: 38217 AN: 39700

South Asian (SAS) AF: 0.879 AC: 75840 AN: 86258

European-Finnish (FIN) AF: 0.931 AC: 49730 AN: 53420

Middle Eastern (MID) AF: 0.951 AC: 5487 AN: 5768

European-Non Finnish (NFE) AF: 0.911 AC: 1012501 AN: 1112012

Other (OTH) AF: 0.914 AC: 55222 AN: 60394

GnomAD4 genome AF: 0.931 AC: 141679 AN: 152178 Hom.: 66000 Cov.: 30 AF XY: 0.932 AC XY: 69290 AN XY: 74372

African (AFR) AF: 0.961 AC: 39886 AN: 41516

American (AMR) AF: 0.921 AC: 14084 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3265 AN: 3468

East Asian (EAS) AF: 0.963 AC: 4966 AN: 5158

South Asian (SAS) AF: 0.876 AC: 4215 AN: 4810

European-Finnish (FIN) AF: 0.936 AC: 9926 AN: 10606

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.915 AC: 62251 AN: 68014

Other (OTH) AF: 0.933 AC: 1967 AN: 2108

Alfa AF: 0.923 Hom.: 170006

Bravo AF: 0.932

Asia WGS AF: 0.905 AC: 3150 AN: 3478

EpiCase AF: 0.917

EpiControl AF: 0.922

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (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	-0.54
CADD	Benign	7.2
DANN	Benign	0.73
PhyloP100		0.83
Mutation Taster		=93/7	polymorphism (auto)

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: rs6599242; hg19: chr3-38739845; COSMIC: COSV108261211;