chr2-166238220-G-C

Position:

• chr2-166238220-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.3675C>G​(p.Ile1225Met) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1225I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.750

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0885551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3675C>G	p.Ile1225Met	missense_variant	20/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.612-9975G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3675C>G	p.Ile1225Met	missense_variant	20/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1290-9975G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	8.6
DANN	Benign	0.81
DEOGEN2	Uncertain	0.48	.;T;.;.;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.089	T;T;T;T;T;T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.7	.;L;.;.;L;L
MutationTaster	Benign	0.55	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.020	N;N;.;.;.;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;D;.;.;.;T
Sift4G	Benign	0.22	T;T;.;.;.;T
Vest4		0.36
MutPred		0.37		Loss of ubiquitination at K1212 (P = 0.1287);.;Loss of ubiquitination at K1212 (P = 0.1287);Loss of ubiquitination at K1212 (P = 0.1287);.;.;
MVP		0.35
MPC		0.12
ClinPred		0.15	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs77144869; hg19: chr2-167094730;