2-166204368-G-A

Variant names:

• chr2-166204368-G-A
• rs187558439
• NM_001365536.1:c.4495C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.4495C>T​(p.Arg1499*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,605,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000292931: Published functional studies demonstrate that R1488X results in a non-functional channel (Wen et al., 2018)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1499R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN9A NM_001365536.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.671
• Publications: 4 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000292931: Published functional studies demonstrate that R1488X results in a non-functional channel (Wen et al., 2018); This variant is associated with the following publications: (PMID: 18070140, 21041956, 25525159, 30037327, 17470132, 19304393, 30672368, 37231219, 32468069)
• PP5: Variant 2-166204368-G-A is Pathogenic according to our data. Variant chr2-166204368-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 245799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4495C>T	p.Arg1499*	stop_gained	Exon 25 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4462C>T	p.Arg1488*	stop_gained	Exon 25 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.611+4550G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4495C>T	p.Arg1499*	stop_gained	Exon 25 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4495C>T	p.Arg1499*	stop_gained	Exon 25 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4462C>T	p.Arg1488*	stop_gained	Exon 25 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151796 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249298 AF XY: 0.00000740

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1454182 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 723286

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.0000449 AC: 2 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39504

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1107166

Other (OTH) AF: 0.00 AC: 0 AN: 60066

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151796 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74130

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67828

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000890 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
1	-	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		0.67
Vest4		0.98
GERP RS		0.91
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs187558439; hg19: chr2-167060878; COSMIC: COSV107324072;