2-166405654-C-G

Position:

• chr2-166405654-C-G

Variant summary

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

The NM_002976.4(SCN7A):​c.4975G>C​(p.Asp1659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.529

Genes affected

SCN7A (HGNC:10594): (sodium voltage-gated channel alpha subunit 7) This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

SCN7A (HGNC:):

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=0.23009363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4	c.4975G>C	p.Asp1659His	missense_variant	26/26	ENST00000643258.1	NP_002967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN7A	ENST00000643258.1	c.4975G>C	p.Asp1659His	missense_variant	26/26		NM_002976.4	ENSP00000496114.1
SCN7A	ENST00000441411.2	c.4975G>C	p.Asp1659His	missense_variant	25/25	1		ENSP00000403846.2
SCN7A	ENST00000424326.5	n.*2780G>C		non_coding_transcript_exon_variant	26/26	1		ENSP00000396600.1
SCN7A	ENST00000424326.5	n.*2780G>C		3_prime_UTR_variant	26/26	1		ENSP00000396600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.4975G>C (p.D1659H) alteration is located in exon 25 (coding exon 24) of the SCN7A gene. This alteration results from a G to C substitution at nucleotide position 4975, causing the aspartic acid (D) at amino acid position 1659 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.00096	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T;T;T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	.;T;.;.;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.0	M;M;M;M;M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	.;.;N;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0010	.;.;D;.;.
Sift4G	Benign	0.12	T;T;T;.;.
Polyphen		0.76	P;P;P;P;P
Vest4		0.081
MutPred		0.30		Loss of disorder (P = 0.1236);Loss of disorder (P = 0.1236);Loss of disorder (P = 0.1236);Loss of disorder (P = 0.1236);Loss of disorder (P = 0.1236);
MVP		0.83
MPC		0.088
ClinPred		0.59	D
GERP RS		1.9
Varity_R		0.12
gMVP		0.41

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: chr2-167262164;