3-38725211-G-T

Position:

• chr3-38725211-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006514.4(SCN10A):​c.3191C>A​(p.Thr1064Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1064M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03904006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.3191C>A	p.Thr1064Lys	missense_variant	18/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.3191C>A	p.Thr1064Lys	missense_variant	18/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.3215C>A	p.Thr1072Lys	missense_variant	18/28
SCN10A	ENST00000643924.1	c.3188C>A	p.Thr1063Lys	missense_variant	17/27			A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.4
DANN	Benign	0.17
DEOGEN2	Benign	0.033	T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00038	N
LIST_S2	Benign	0.34	.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.69	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.39	N;.;.;.
REVEL	Benign	0.20
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	0.86	T;.;.;.
Polyphen		0.0	B;.;B;.
Vest4		0.053
MutPred		0.44		Gain of ubiquitination at T1064 (P = 0.0018);Gain of ubiquitination at T1064 (P = 0.0018);Gain of ubiquitination at T1064 (P = 0.0018);.;
MVP		0.41
MPC		0.070
ClinPred		0.039	T
GERP RS		2.4
Varity_R		0.041
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774803610; hg19: chr3-38766702; COSMIC: COSV71862380;