rs145694222

Variant names:

• chr3-38726851-C-G
• rs145694222
• NM_006514.4:c.2842G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-38726851-C-G
• chr3-38726851-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006514.4(SCN10A):​c.2842G>C​(p.Val948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,614,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V948M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.346
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038193822).
• BP6: Variant 3-38726851-C-G is Benign according to our data. Variant chr3-38726851-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407748.
• BS2: High AC in GnomAd4 at 64 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.2842G>C	p.Val948Leu	missense	Exon 17 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.2842G>C	p.Val948Leu	missense	Exon 16 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.2548G>C	p.Val850Leu	missense	Exon 15 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.2842G>C	p.Val948Leu	missense	Exon 17 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.2842G>C	p.Val948Leu	missense	Exon 16 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.2869G>C	p.Val957Leu	missense	Exon 17 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000490 AC: 123 AN: 251218 AF XY: 0.000516

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000899

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000841 AC: 1230 AN: 1461758 Hom.: 1 Cov.: 33 AF XY: 0.000820 AC XY: 596 AN XY: 727160

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000246 AC: 11 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00107 AC: 1192 AN: 1111902

Other (OTH) AF: 0.000381 AC: 23 AN: 60388

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74476

African (AFR) AF: 0.000265 AC: 11 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000533

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.00131

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Episodic pain syndrome, familial, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.090	N
PhyloP100		0.35
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.16
Sift	Benign	0.29	T
Sift4G	Benign	0.42	T
Polyphen		0.12	B
Vest4		0.063
MutPred		0.70		Loss of glycosylation at P952 (P = 0.0476)
MVP		0.62
MPC		0.061
ClinPred		0.0023	T
GERP RS		2.5
Varity_R		0.061
gMVP		0.11
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: rs145694222; hg19: chr3-38768342;