chr2-166204470-G-T

Variant names:

• chr2-166204470-G-T
• rs1553474406
• NM_001365536.1:c.4399-6C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001365536.1(SCN9A):​c.4399-6C>A variant causes a splice region, intron 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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN9A NM_001365536.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001626
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.370
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-166204470-G-T is Benign according to our data. Variant chr2-166204470-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471129.

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.4399-6C>A		splice_region intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.4366-6C>A		splice_region intron	N/A	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.611+4652G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4399-6C>A		splice_region intron	N/A	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.4399-6C>A		splice_region intron	N/A	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.4366-6C>A		splice_region intron	N/A	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1357020 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 675860

African (AFR) AF: 0.00 AC: 0 AN: 30122

American (AMR) AF: 0.00 AC: 0 AN: 35484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23898

East Asian (EAS) AF: 0.00 AC: 0 AN: 38814

South Asian (SAS) AF: 0.00 AC: 0 AN: 74038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3838

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042532

Other (OTH) AF: 0.00 AC: 0 AN: 56168

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4366-6C>A intronic variant results from a C to A substitution 6 nucleotides upstream from coding exon 24 in the SCN9A gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.43
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
SpliceAI score (max)		0.060		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: rs1553474406; hg19: chr2-167060980;