rs1064793841

Positions:

• chr20-63350183-CA-TG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The ENST00000370263.9(CHRNA4):​c.1227_1228inv​(p.Val410Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. C409C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNA4 ENST00000370263.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0670

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 20-63350183-CA-TG is Benign according to our data. Variant chr20-63350183-CA-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411850.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1227_1228inv	p.Val410Ile	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.699_700inv	p.Val234Ile	missense_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2	n.1436_1437inv		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1227_1228inv	p.Val410Ile	missense_variant	5/6	1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064793841; hg19: chr20-61981535;