rs1064796825

Variant names:

• chr2-166204108-G-A
• rs1064796825
• NM_001365536.1:c.4621C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166204108-G-A
• chr2-166204108-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001365536.1(SCN9A):​c.4621C>T​(p.Gln1541*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -4.80
• Publications: 1 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166204108-G-A is Pathogenic according to our data. Variant chr2-166204108-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3381859.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.4621C>T	p.Gln1541*	stop_gained	Exon 26 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.4588C>T	p.Gln1530*	stop_gained	Exon 26 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.611+4290G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4621C>T	p.Gln1541*	stop_gained	Exon 26 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.4621C>T	p.Gln1541*	stop_gained	Exon 26 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.4588C>T	p.Gln1530*	stop_gained	Exon 26 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000252 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.028	N
PhyloP100		-4.8
Vest4		0.88
GERP RS		-2.7
Mutation Taster		=13/187	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064796825; hg19: chr2-167060618;