rs1001051115

chr17-63961396-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000334.4(SCN4A):c.1642T>C(p.Trp548Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.32

Genes affected

SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

LOC105371858 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.1642T>C	p.Trp548Arg	missense_variant	11/24	ENST00000435607.3
LOC105371858	XR_001752969.2	n.68+674A>G		intron_variant, non_coding_transcript_variant
LOC105371858	XR_934910.3	n.68+674A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.1642T>C	p.Trp548Arg	missense_variant	11/24	1	NM_000334.4	P1
SCN4A	ENST00000581514.1	n.298T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461542 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.096	T
Polyphen		0.14	B
Vest4		0.94
MutPred		0.59		Gain of disorder (P = 0.0477);
MVP		0.92
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.87

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: rs1001051115; hg19: chr17-62038756;