chr2-166272421-G-A

Variant names:

• chr2-166272421-G-A
• rs145258166
• NM_001365536.1:c.3329C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365536.1(SCN9A):​c.3329C>T​(p.Ser1110Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,598,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. S1110P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000092 (1 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 9.56
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028585255).

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.3329C>T	p.Ser1110Leu	missense	Exon 17 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.3296C>T	p.Ser1099Leu	missense	Exon 17 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.870-4667G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3329C>T	p.Ser1110Leu	missense	Exon 17 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.3329C>T	p.Ser1110Leu	missense	Exon 17 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.3296C>T	p.Ser1099Leu	missense	Exon 17 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151960 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000478

GnomAD2 exomes AF: 0.000194 AC: 46 AN: 236918 AF XY: 0.000187

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.000520

GnomAD4 exome AF: 0.0000920 AC: 133 AN: 1445958 Hom.: 1 Cov.: 31 AF XY: 0.0000934 AC XY: 67 AN XY: 717158

African (AFR) AF: 0.00229 AC: 76 AN: 33194

American (AMR) AF: 0.000183 AC: 8 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39274

South Asian (SAS) AF: 0.0000593 AC: 5 AN: 84330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000300 AC: 33 AN: 1101680

Other (OTH) AF: 0.000151 AC: 9 AN: 59780

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152078 Hom.: 0 Cov.: 31 AF XY: 0.000619 AC XY: 46 AN XY: 74312

African (AFR) AF: 0.00217 AC: 90 AN: 41502

American (AMR) AF: 0.000197 AC: 3 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000771

ESP6500AA AF: 0.00243 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000240 AC: 29

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Vest4		0.56
MVP		0.89
MPC		0.46
ClinPred		0.21	T
GERP RS		5.4
Varity_R		0.70
gMVP		0.33
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs145258166; hg19: chr2-167128931; COSMIC: COSV57609662; COSMIC: COSV57609662;