chr2-166204478-C-G

Variant names:

• chr2-166204478-C-G
• rs112927502
• NM_001365536.1:c.4399-14G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001365536.1(SCN9A):​c.4399-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 492,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 31)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4399-14G>C		intron_variant	Intron 24 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4399-14G>C		intron_variant	Intron 24 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4399-14G>C		intron_variant	Intron 24 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4366-14G>C		intron_variant	Intron 24 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4366-14G>C		intron_variant	Intron 24 of 26			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000203 AC: 1 AN: 492506 Hom.: 0 Cov.: 13 AF XY: 0.00000389 AC XY: 1 AN XY: 257044

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11360

American (AMR) AF: 0.00 AC: 0 AN: 20610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11828

East Asian (EAS) AF: 0.00 AC: 0 AN: 22712

South Asian (SAS) AF: 0.00 AC: 0 AN: 41104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1816

European-Non Finnish (NFE) AF: 0.00000304 AC: 1 AN: 329452

Other (OTH) AF: 0.00 AC: 0 AN: 24290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.29
DANN	Benign	0.57
PhyloP100		-1.1

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

Other links and lift over

dbSNP: rs112927502; hg19: chr2-167060988;