chr2-166198690-G-C

Variant names:

• chr2-166198690-G-C
• rs201640210
• NM_001365536.1:c.5949C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365536.1(SCN9A):​c.5949C>G​(p.Ser1983Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,593,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. S1983I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.21
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025282294).
• BP6: Variant 2-166198690-G-C is Benign according to our data. Variant chr2-166198690-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246381.
• BS2: High Homozygotes in GnomAd4 at 2 AD,SD,AR gene

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.5949C>G	p.Ser1983Arg	missense	Exon 27 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.5916C>G	p.Ser1972Arg	missense	Exon 27 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.432-949G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.5949C>G	p.Ser1983Arg	missense	Exon 27 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.5949C>G	p.Ser1983Arg	missense	Exon 27 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.5916C>G	p.Ser1972Arg	missense	Exon 27 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000781 AC: 18 AN: 230498 AF XY: 0.0000562

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000946

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000277 AC: 40 AN: 1441596 Hom.: 0 Cov.: 31 AF XY: 0.0000238 AC XY: 17 AN XY: 715484

African (AFR) AF: 0.000745 AC: 24 AN: 32202

American (AMR) AF: 0.0000988 AC: 4 AN: 40502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1104098

Other (OTH) AF: 0.0000671 AC: 4 AN: 59586

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152110 Hom.: 2 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74364

African (AFR) AF: 0.00113 AC: 47 AN: 41520

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.025	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.31
Sift	Benign	0.16	T
Sift4G	Benign	0.54	T
Vest4		0.043
MutPred		0.24		Loss of phosphorylation at S1972 (P = 4e-04)
MVP		0.67
MPC		0.13
ClinPred		0.022	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.16
Mutation Taster		=63/37	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: rs201640210; hg19: chr2-167055200;