2-166281778-G-A

Variant names:

• chr2-166281778-G-A
• rs200174262
• NM_001365536.1:c.2005C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001365536.1(SCN9A):​c.2005C>T​(p.Arg669Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R669H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.232
• Publications: 3 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030504197).
• BP6: Variant 2-166281778-G-A is Benign according to our data. Variant chr2-166281778-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449780.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.2005C>T	p.Arg669Cys	missense	Exon 13 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1972C>T	p.Arg658Cys	missense	Exon 13 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+4531G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2005C>T	p.Arg669Cys	missense	Exon 13 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.2005C>T	p.Arg669Cys	missense	Exon 13 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1972C>T	p.Arg658Cys	missense	Exon 13 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 247644 AF XY: 0.0000968

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000637 AC: 93 AN: 1460354 Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36 AN XY: 726410

African (AFR) AF: 0.00105 AC: 35 AN: 33394

American (AMR) AF: 0.0000672 AC: 3 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111210

Other (OTH) AF: 0.000133 AC: 8 AN: 60318

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74316

African (AFR) AF: 0.00116 AC: 48 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67984

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000250 Hom.: 0

Bravo AF: 0.000427

ESP6500AA AF: 0.00134 AC: 5

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.23
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.032	D
Sift4G	Uncertain	0.023	D
Polyphen		0.014	B
Vest4		0.42
MVP		0.81
MPC		0.17
ClinPred		0.071	T
GERP RS		2.7
Varity_R		0.14
gMVP		0.46
Mutation Taster		=61/39	polymorphism

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: rs200174262; hg19: chr2-167138288;