chr3-38701840-C-T

Variant names:

• chr3-38701840-C-T
• rs151182542
• NM_006514.4:c.4656G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006514.4(SCN10A):​c.4656G>A​(p.Ala1552Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,597,466 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: SCN10A NM_006514.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003792
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.40
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-38701840-C-T is Benign according to our data. Variant chr3-38701840-C-T is described in ClinVar as Benign. ClinVar VariationId is 506666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BS2: High AC in GnomAd4 at 622 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.4656G>A	p.Ala1552Ala	splice_region synonymous	Exon 27 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.4653G>A	p.Ala1551Ala	splice_region synonymous	Exon 26 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.4362G>A	p.Ala1454Ala	splice_region synonymous	Exon 25 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.4656G>A	p.Ala1552Ala	splice_region synonymous	Exon 27 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.4653G>A	p.Ala1551Ala	splice_region synonymous	Exon 26 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.4680G>A	p.Ala1560Ala	splice_region synonymous	Exon 27 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00118 AC: 284 AN: 239864 AF XY: 0.000990

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000862

GnomAD4 exome AF: 0.000537 AC: 776 AN: 1445112 Hom.: 6 Cov.: 31 AF XY: 0.000508 AC XY: 364 AN XY: 716526

African (AFR) AF: 0.0142 AC: 468 AN: 33024

American (AMR) AF: 0.000948 AC: 41 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.000626 AC: 16 AN: 25578

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 39024

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83264

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53098

Middle Eastern (MID) AF: 0.00473 AC: 27 AN: 5710

European-Non Finnish (NFE) AF: 0.000104 AC: 115 AN: 1102436

Other (OTH) AF: 0.00174 AC: 104 AN: 59724

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00416 AC XY: 310 AN XY: 74504

African (AFR) AF: 0.0130 AC: 540 AN: 41574

American (AMR) AF: 0.00333 AC: 51 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00171 Hom.: 3

Bravo AF: 0.00479

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.27
PhyloP100		-2.4
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.098
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: rs151182542; hg19: chr3-38743331; COSMIC: COSV101479212;