chr2-166272694-T-C

Variant names:

• chr2-166272694-T-C
• rs201979706
• NM_001365536.1:c.3056A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365536.1(SCN9A):​c.3056A>G​(p.Lys1019Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,598,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K1019K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0400
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11476654).

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.3056A>G	p.Lys1019Arg	missense	Exon 17 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3023A>G	p.Lys1008Arg	missense	Exon 17 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.870-4394T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3056A>G	p.Lys1019Arg	missense	Exon 17 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3056A>G	p.Lys1019Arg	missense	Exon 17 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3023A>G	p.Lys1008Arg	missense	Exon 17 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151774 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000294 AC: 7 AN: 237722 AF XY: 0.0000233

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000640

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 100 AN: 1446318 Hom.: 0 Cov.: 31 AF XY: 0.0000711 AC XY: 51 AN XY: 717688

African (AFR) AF: 0.00 AC: 0 AN: 32580

American (AMR) AF: 0.00 AC: 0 AN: 42104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 83494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000824 AC: 91 AN: 1104760

Other (OTH) AF: 0.000151 AC: 9 AN: 59630

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151774 Hom.: 0 Cov.: 31 AF XY: 0.0000810 AC XY: 6 AN XY: 74070

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.0069
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.040
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.075	T
Sift4G	Benign	0.24	T
Vest4		0.14
MVP		0.53
MPC		0.099
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.14
gMVP		0.11
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201979706; hg19: chr2-167129204;