rs774903062

Variant names:

• chr2-166284824-A-C
• rs774903062
• NM_001365536.1:c.1603T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001365536.1(SCN9A):​c.1603T>G​(p.Ser535Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S535L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense, splice_region
• Scores: Splicing: ADA: 0.7714
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.88
• Publications: 1 publications found

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. 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
	SCN9A	NM_001365536.1	MANE Select	c.1603T>G	p.Ser535Ala	missense splice_region	Exon 12 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1603T>G	p.Ser535Ala	missense splice_region	Exon 12 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+7577A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1603T>G	p.Ser535Ala	missense splice_region	Exon 12 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.1603T>G	p.Ser535Ala	missense splice_region	Exon 12 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1603T>G	p.Ser535Ala	missense splice_region	Exon 12 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000221 AC: 5 AN: 226532 AF XY: 0.00000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1442042 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 716550

African (AFR) AF: 0.00 AC: 0 AN: 32394

American (AMR) AF: 0.000146 AC: 6 AN: 41176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.00 AC: 0 AN: 83900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105460

Other (OTH) AF: 0.00 AC: 0 AN: 59552

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.36	T
Polyphen		0.59	P
Vest4		0.64
MVP		0.77
MPC		0.34
ClinPred		0.67	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.44
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.63
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: rs774903062; hg19: chr2-167141334;