NM_001365536.1:c.4701C>T

Variant names:

• chr2-166204028-G-A
• rs201067234
• NM_001365536.1:c.4701C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001365536.1(SCN9A):​c.4701C>T​(p.Ile1567Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.419
• 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-166204028-G-A is Benign according to our data. Variant chr2-166204028-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 471133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.4701C>T	p.Ile1567Ile	synonymous	Exon 26 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4668C>T	p.Ile1556Ile	synonymous	Exon 26 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.611+4210G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4701C>T	p.Ile1567Ile	synonymous	Exon 26 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4701C>T	p.Ile1567Ile	synonymous	Exon 26 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4668C>T	p.Ile1556Ile	synonymous	Exon 26 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247954 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456264 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724684

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107488

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.3
DANN	Benign	0.70
PhyloP100		0.42
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs201067234; hg19: chr2-167060538;