chr2-166278220-T-C

Variant names:

• chr2-166278220-T-C
• rs201890240
• NM_001365536.1:c.2437A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.2437A>G​(p.Ser813Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,612,946 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S813N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.17
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011776537).
• BP6: Variant 2-166278220-T-C is Benign according to our data. Variant chr2-166278220-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000775 (118/152288) while in subpopulation SAS AF = 0.0238 (115/4824). AF 95% confidence interval is 0.0203. There are 1 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 39 AD,SD,AR gene

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.2437A>G	p.Ser813Gly	missense	Exon 15 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.2404A>G	p.Ser802Gly	missense	Exon 15 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+973T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2437A>G	p.Ser813Gly	missense	Exon 15 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.2437A>G	p.Ser813Gly	missense	Exon 15 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.2404A>G	p.Ser802Gly	missense	Exon 15 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00268 AC: 661 AN: 247084 AF XY: 0.00353

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.00131 AC: 1911 AN: 1460658 Hom.: 39 Cov.: 30 AF XY: 0.00188 AC XY: 1368 AN XY: 726644

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000672 AC: 3 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0210 AC: 1808 AN: 86182

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53178

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111400

Other (OTH) AF: 0.00118 AC: 71 AN: 60340

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000233 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00289 AC: 349

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	Inherited Erythromelalgia (1)
-	-	1	not specified (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.53	N
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	2.3	N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T
Sift4G	Benign	0.63	T
Vest4		0.39
MVP		0.74
MPC		0.11
ClinPred		0.035	T
GERP RS		5.2
PromoterAI		0.024	Neutral
Varity_R		0.31
gMVP		0.78
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs201890240; hg19: chr2-167134730;