3-38702100-G-T

Variant names:

• chr3-38702100-G-T
• rs199931920
• NM_006514.4:c.4396C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006514.4(SCN10A):​c.4396C>A​(p.Gln1466Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1466R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.94
• 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):

• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

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.4396C>A	p.Gln1466Lys	missense	Exon 27 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.4393C>A	p.Gln1465Lys	missense	Exon 26 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.4102C>A	p.Gln1368Lys	missense	Exon 25 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.4396C>A	p.Gln1466Lys	missense	Exon 27 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.4393C>A	p.Gln1465Lys	missense	Exon 26 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.4420C>A	p.Gln1474Lys	missense	Exon 27 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398142 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688788

African (AFR) AF: 0.00 AC: 0 AN: 31278

American (AMR) AF: 0.00 AC: 0 AN: 35336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22124

East Asian (EAS) AF: 0.00 AC: 0 AN: 38944

South Asian (SAS) AF: 0.00 AC: 0 AN: 73968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082170

Other (OTH) AF: 0.00 AC: 0 AN: 57706

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		9.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.93
Sift	Benign	0.033	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.57		Gain of methylation at Q1466 (P = 0.0014)
MVP		0.99
MPC		0.33
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.82
Mutation Taster		=52/48	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: rs199931920; hg19: chr3-38743591;