chr3-38761222-C-T

Variant names:

• chr3-38761222-C-T
• rs146151670
• NM_006514.4:c.853G>A

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.853G>A​(p.Glu285Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,608,048 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).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.53
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013943881).
• BP6: Variant 3-38761222-C-T is Benign according to our data. Variant chr3-38761222-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414621.
• BS2: High AC in GnomAd4 at 78 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.853G>A	p.Glu285Lys	missense	Exon 7 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.853G>A	p.Glu285Lys	missense	Exon 6 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.853G>A	p.Glu285Lys	missense	Exon 6 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.853G>A	p.Glu285Lys	missense	Exon 7 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.853G>A	p.Glu285Lys	missense	Exon 6 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.853G>A	p.Glu285Lys	missense	Exon 7 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.000514 AC: 78 AN: 151832 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000929

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000427 AC: 107 AN: 250782 AF XY: 0.000406

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000758

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000761 AC: 1108 AN: 1456098 Hom.: 0 Cov.: 31 AF XY: 0.000719 AC XY: 521 AN XY: 724390

African (AFR) AF: 0.000120 AC: 4 AN: 33428

American (AMR) AF: 0.0000898 AC: 4 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 31 AN: 25848

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85832

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000950 AC: 1052 AN: 1107914

Other (OTH) AF: 0.000267 AC: 16 AN: 60018

GnomAD4 genome AF: 0.000513 AC: 78 AN: 151950 Hom.: 1 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74306

African (AFR) AF: 0.000120 AC: 5 AN: 41532

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

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: 10574

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

European-Non Finnish (NFE) AF: 0.000929 AC: 63 AN: 67796

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000855 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.00104

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	-	1	SCN10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.8
DANN	Benign	0.45
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.49	N
PhyloP100		-1.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.25
Sift	Benign	0.59	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.42
MPC		0.066
ClinPred		0.0041	T
GERP RS		-1.3
Varity_R		0.041
gMVP		0.61
Mutation Taster		=97/3	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: rs146151670; hg19: chr3-38802713;