rs6746030

Positions:

• chr2-166242648-A-C
• chr2-166242648-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.3481T>G​(p.Trp1161Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1161R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3481T>G	p.Trp1161Gly	missense_variant	19/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.612-5547A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3481T>G	p.Trp1161Gly	missense_variant	19/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1290-5547A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.17	.;T;.;.;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.49	T;.;T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.34	.;N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.80	N;.;.;.;.;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;.;.;.;.;D
Sift4G	Benign	0.16	T;T;.;.;.;T
Vest4		0.14
MutPred		0.62		Gain of disorder (P = 0.0446);.;Gain of disorder (P = 0.0446);Gain of disorder (P = 0.0446);.;.;
MVP		0.29
MPC		0.21
ClinPred		0.30	T
GERP RS		3.8
Varity_R		0.32
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.56		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6746030; hg19: chr2-167099158;