chr2-166311504-T-G

Variant names:

• chr2-166311504-T-G
• NM_001365536.1:c.253A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.253A>C​(p.Lys85Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.178108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.253A>C	p.Lys85Gln	missense_variant	Exon 2 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.253A>C	p.Lys85Gln	missense_variant	Exon 3 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406296 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 695180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Benign	0.17	.;T;.;.;T;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.095	N;N;N;.;N;N;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.41	N;N;.;.;.;N;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.61	T;T;.;.;.;T;.;.
Sift4G	Benign	0.85	T;T;.;.;.;T;.;.
Vest4		0.21
MutPred		0.43		Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);Loss of ubiquitination at K85 (P = 0.013);
MVP		0.60
MPC		0.15
ClinPred		0.38	T
GERP RS		5.4
Varity_R		0.13
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-167168014;