NM_001365536.1:c.3019C>T

Variant names:

• chr2-166272731-G-A
• rs121908910
• NM_001365536.1:c.3019C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_001365536.1(SCN9A):​c.3019C>T​(p.Arg1007Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,584,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1007H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.31
• Publications: 16 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.

• PP5: Variant 2-166272731-G-A is Pathogenic according to our data. Variant chr2-166272731-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6356.

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.3019C>T	p.Arg1007Cys	missense	Exon 17 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.2986C>T	p.Arg996Cys	missense	Exon 17 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.870-4357G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3019C>T	p.Arg1007Cys	missense	Exon 17 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.3019C>T	p.Arg1007Cys	missense	Exon 17 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.2986C>T	p.Arg996Cys	missense	Exon 17 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151586 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 226882 AF XY: 0.0000245

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000589

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 28 AN: 1432680 Hom.: 0 Cov.: 31 AF XY: 0.0000225 AC XY: 16 AN XY: 709628

African (AFR) AF: 0.0000312 AC: 1 AN: 32084

American (AMR) AF: 0.0000746 AC: 3 AN: 40228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24510

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80878

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1098646

Other (OTH) AF: 0.0000339 AC: 2 AN: 59002

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151702 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74092

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.000132 AC: 2 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10498

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000849 Hom.: 0

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Paroxysmal extreme pain disorder (2)
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	0.11
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.3
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Benign	0.094	T
Sift4G	Benign	0.19	T
Vest4		0.24
MVP		0.61
MPC		0.18
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.17
gMVP		0.40
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908910; hg19: chr2-167129241;