2-166204084-A-T

Variant names:

• chr2-166204084-A-T
• rs202084411
• NM_001365536.1:c.4645T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001365536.1(SCN9A):​c.4645T>A​(p.Trp1549Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1549Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.17
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-166204084-A-T is Benign according to our data. Variant chr2-166204084-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1152102.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4645T>A	p.Trp1549Arg	missense	Exon 26 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.4612T>A	p.Trp1538Arg	missense	Exon 26 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.611+4266A>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4645T>A	p.Trp1549Arg	missense	Exon 26 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.4645T>A	p.Trp1549Arg	missense	Exon 26 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.4612T>A	p.Trp1538Arg	missense	Exon 26 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	0.30
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.81	L
PhyloP100		4.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.67
Sift	Benign	0.92	T
Sift4G	Benign	0.36	T
Vest4		0.82
MutPred		0.65		Loss of catalytic residue at L1536 (P = 0.0064)
MVP		0.72
MPC		0.24
ClinPred		0.78	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.72
Mutation Taster		=3/97	disease causing

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: rs202084411; hg19: chr2-167060594;