chr2-166284824-A-C

Variant names:

• chr2-166284824-A-C
• rs774903062
• NM_001365536.1:c.1603T>G

Variant summary

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

The NM_001365536.1(SCN9A):​c.1603T>G​(p.Ser535Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense, splice_region
• Scores: Splicing: ADA: 0.7714
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.88

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: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1603T>G	p.Ser535Ala	missense_variant, splice_region_variant	Exon 12 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000221 AC: 5 AN: 226532 Hom.: 0 AF XY: 0.00000810 AC XY: 1 AN XY: 123408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1442042 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 716550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000146

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 471087). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is present in population databases (rs774903062, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 535 of the SCN9A protein (p.Ser535Ala). -

not provided Uncertain:1

Nov 18, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.;.;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T;.;T;T;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N;.;.;.;.;N;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;.;.;.;D;.
Sift4G	Benign	0.36	T;T;.;.;.;T;.
Polyphen		0.59	.;P;.;.;P;.;.
Vest4		0.64
MVP		0.77
MPC		0.34
ClinPred		0.67	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.63
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: rs774903062; hg19: chr2-167141334;