rs771936944

Variant names:

• chr20-63361113-AGCAGCAGCAGCGGCG-A
• rs771936944
• NM_000744.7:c.38_52delCGCCGCTGCTGCTGC

Your query was ambiguous. Multiple possible variants found:

• chr20-63361113-AGCAGCAGCAGCGGCG-A
• chr20-63361113-AGCAGCAGCAGCGGCG-AGCAGCAGCAGCGGCGGCAGCAGCAGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000744.7(CHRNA4):​c.38_52delCGCCGCTGCTGCTGC​(p.Pro13_Leu17del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000453 in 1,325,072 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P13P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

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]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000203900 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000744.7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.38_52delCGCCGCTGCTGCTGC	p.Pro13_Leu17del	disruptive_inframe_deletion	Exon 1 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NR_046317.2	n.222_236delCGCCGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 6
CHRNA4	NM_001256573.2	c.-471+49_-471+63delCGCCGCTGCTGCTGC		intron_variant	Intron 1 of 5		NP_001243502.1
LOC100130587	NR_110634.1	n.183-696_183-682delAGCGGCGGCAGCAGC		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.38_52delCGCCGCTGCTGCTGC	p.Pro13_Leu17del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000453 AC: 6 AN: 1325072 Hom.: 0 AF XY: 0.00000613 AC XY: 4 AN XY: 652624

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26884

American (AMR) AF: 0.00 AC: 0 AN: 28368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23512

East Asian (EAS) AF: 0.00 AC: 0 AN: 29794

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 73196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00000475 AC: 5 AN: 1051894

Other (OTH) AF: 0.00 AC: 0 AN: 55022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000008), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1307578). This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.38_52del, results in the deletion of 5 amino acid(s) of the CHRNA4 protein (p.Pro13_Leu17del), but otherwise preserves the integrity of the reading frame. -

not provided Uncertain:1

Sep 18, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In-frame deletion of 5 amino acids in a non-repeat region; 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

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

Other links and lift over

dbSNP: rs771936944; hg19: chr20-61992465;