chr2-166272422-A-G

Position:

• chr2-166272422-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.3328T>C​(p.Ser1110Pro) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3328T>C	p.Ser1110Pro	missense_variant	17/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3328T>C	p.Ser1110Pro	missense_variant	17/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3328T>C	p.Ser1110Pro	missense_variant	17/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3295T>C	p.Ser1099Pro	missense_variant	17/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3295T>C	p.Ser1099Pro	missense_variant	17/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brainstem MRI signal intensity;C4316903:Generalized non-motor (absence) seizure Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.;.;D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;.;.;.;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.;.;.;.;D
Sift4G	Benign	0.077	T;T;.;.;.;T
Vest4		0.54
MutPred		0.32		Loss of phosphorylation at S1099 (P = 0.0049);.;Loss of phosphorylation at S1099 (P = 0.0049);Loss of phosphorylation at S1099 (P = 0.0049);.;.;
MVP		0.88
MPC		0.60
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553486581; hg19: chr2-167128932;