rs375926577

Variant names:

• chr3-38722325-C-T
• rs375926577
• NM_006514.4:c.3440G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006514.4(SCN10A):​c.3440G>A​(p.Arg1147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R1147C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.483
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08252558).
• BP6: Variant 3-38722325-C-T is Benign according to our data. Variant chr3-38722325-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 532089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 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.3440G>A	p.Arg1147His	missense	Exon 20 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.3437G>A	p.Arg1146His	missense	Exon 19 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.3146G>A	p.Arg1049His	missense	Exon 18 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.3440G>A	p.Arg1147His	missense	Exon 20 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.3437G>A	p.Arg1146His	missense	Exon 19 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.3464G>A	p.Arg1155His	missense	Exon 20 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251446 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727202

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111916

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74290

African (AFR) AF: 0.0000483 AC: 2 AN: 41388

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000947 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.48
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.17	B
Vest4		0.20
MVP		0.72
MPC		0.076
ClinPred		0.059	T
GERP RS		2.3
Varity_R		0.070
gMVP		0.36
Mutation Taster		=90/10	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: rs375926577; hg19: chr3-38763816; COSMIC: COSV101479488;