2-166477575-G-C

Variant names:

• chr2-166477575-G-C
• rs7565062
• NM_002976.4:c.122C>G

Variant summary

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

The NM_002976.4(SCN7A):​c.122C>G​(p.Thr41Ser) 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. 17/22 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. T41N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 40 publications found

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 Gene-Disease associations (from GenCC):

• holoprosencephaly

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

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 (MetaRNN=0.02957502).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002976.4. 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
	SCN7A	NM_002976.4	MANE Select	c.122C>G	p.Thr41Ser	missense	Exon 3 of 26	NP_002967.2	Q01118
	SCN7A	NR_045628.1		n.252C>G		non_coding_transcript_exon	Exon 2 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN7A	ENST00000643258.1	MANE Select	c.122C>G	p.Thr41Ser	missense	Exon 3 of 26	ENSP00000496114.1	Q01118
	SCN7A	ENST00000441411.2	TSL:1	c.122C>G	p.Thr41Ser	missense	Exon 2 of 25	ENSP00000403846.2	Q01118
	SCN7A	ENST00000424326.5	TSL:1	n.122C>G		non_coding_transcript_exon	Exon 2 of 26	ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 56508

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.35
DANN	Benign	0.45
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Benign	-2.2	N
PhyloP100		-0.19
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.17
Sift	Benign	0.40	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.021
MutPred		0.26		Loss of glycosylation at T41 (P = 0.0416)
MVP		0.48
MPC		0.032
ClinPred		0.074	T
GERP RS		1.1
Varity_R		0.019
gMVP		0.049
Mutation Taster		=99/1	polymorphism

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: rs7565062; hg19: chr2-167334085;