rs74341575

Variant names:

• chr8-27463370-C-A
• rs74341575
• NM_000742.4:c.1073G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-27463370-C-A
• chr8-27463370-C-G
• chr8-27463370-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_000742.4(CHRNA2):​c.1073G>T​(p.Ser358Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.08

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3054665).
• BP6: Variant 8-27463370-C-A is Benign according to our data. Variant chr8-27463370-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1073G>T	p.Ser358Ile	missense_variant	Exon 6 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1073G>T	p.Ser358Ile	missense_variant	Exon 6 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000798 AC: 20 AN: 250536 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461764 Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44 AN XY: 727160

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000579 AC: 23 AN: 39700

Gnomad4 SAS exome AF: 0.000348 AC: 30 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53298

Gnomad4 NFE exome AF: 0.00000540 AC: 6 AN: 1112010

Gnomad4 Remaining exome AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74440

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000581 AC: 0.000580945 AN: 0.000580945

Gnomad4 SAS AF: 0.000415 AC: 0.000414766 AN: 0.000414766

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588132 AN: 0.0000588132

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 07, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser358Ile (AGC>ATC): c.1073 G>T in exon 6 of the CHRNA2 gene (NM_000742.3). The S358I missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this amino acid substitution occurs at a position that is not highly conserved across species and does not occur within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. The variant is found in INFANT-EPI panel(s). -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.45	B;.;.
Vest4		0.36
MutPred		0.44		Loss of disorder (P = 0.0048);.;.;
MVP		0.92
MPC		0.68
ClinPred		0.76	D
GERP RS		4.0
Varity_R		0.64
gMVP		0.56
Mutation Taster		=82/18	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

Publications

LitVar

Other links and lift over

dbSNP: rs74341575; hg19: chr8-27320887;