chr2-166304279-A-G

Position:

• chr2-166304279-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001365536.1(SCN9A):​c.647T>C​(p.Phe216Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.32

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]

SCN9A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-166304279-A-G is Pathogenic according to our data. Variant chr2-166304279-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6365.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-166304279-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.647T>C	p.Phe216Ser	missense_variant	6/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.647T>C	p.Phe216Ser	missense_variant	6/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.647T>C	p.Phe216Ser	missense_variant	6/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.647T>C	p.Phe216Ser	missense_variant	6/27	5		ENSP00000386306.1
SCN9A	ENST00000454569.6	c.647T>C	p.Phe216Ser	missense_variant	6/15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.647T>C	p.Phe216Ser	missense_variant	7/11	1		ENSP00000393141.2
SCN9A	ENST00000645907.1	c.597-157T>C		intron_variant				ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary erythromelalgia Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 14, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;D;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.8	D;.;.;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;D;D
Sift4G	Uncertain	0.013	D;D;.;.;.
Vest4		0.98
MutPred		0.94		Loss of stability (P = 0.0088);Loss of stability (P = 0.0088);Loss of stability (P = 0.0088);Loss of stability (P = 0.0088);Loss of stability (P = 0.0088);
MVP		0.95
MPC		0.75
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80356469; hg19: chr2-167160789;