2-166272533-C-G

Position:

• chr2-166272533-C-G

Variant summary

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

The NM_001365536.1(SCN9A):​c.3217G>C​(p.Asp1073His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1073N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3217G>C	p.Asp1073His	missense_variant	17/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.870-4555C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3217G>C	p.Asp1073His	missense_variant	17/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1548-4555C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461268 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.48	T;.;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.2	.;L;.;.;L;L
MutationTaster	Benign	0.53	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;.;.;.;.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;.;.;.;.;D
Sift4G	Benign	0.079	T;T;.;.;.;T
Vest4		0.36
MutPred		0.46		Loss of methylation at K1057 (P = 0.1107);.;Loss of methylation at K1057 (P = 0.1107);Loss of methylation at K1057 (P = 0.1107);.;.;
MVP		0.70
MPC		0.37
ClinPred		0.83	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.23
gMVP		0.34

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: rs201389358; hg19: chr2-167129043;