20-63356386-G-T

Variant names:

• chr20-63356386-G-T
• rs140239470
• NM_000744.7:c.258C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000370263.9(CHRNA4):​c.258C>A​(p.Asn86Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N86N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHRNA4 ENST00000370263.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.602
• Publications: 1 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370263.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.258C>A	p.Asn86Lys	missense	Exon 3 of 6	NP_000735.1
	CHRNA4	NR_046317.2		n.442C>A		non_coding_transcript_exon	Exon 3 of 6
	CHRNA4	NM_001256573.2		c.-289C>A		5_prime_UTR	Exon 3 of 6	NP_001243502.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.258C>A	p.Asn86Lys	missense	Exon 3 of 6	ENSP00000359285.4
	CHRNA4	ENST00000467563.3	TSL:1	n.310C>A		non_coding_transcript_exon	Exon 3 of 6
	CHRNA4	ENST00000627000.1	TSL:1	n.258C>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000486914.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000439 AC: 1 AN: 227686 AF XY: 0.00000813

Gnomad AFR exome AF: 0.0000711

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448128 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 718744

African (AFR) AF: 0.0000601 AC: 2 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 43410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.00 AC: 0 AN: 83622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105986

Other (OTH) AF: 0.00 AC: 0 AN: 59818

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.096
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.60
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.86		Gain of methylation at N86 (P = 0.0209)
MVP		0.86
MPC		1.3
ClinPred		0.99	D
GERP RS		1.3
Varity_R		0.71
gMVP		0.84
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140239470; hg19: chr20-61987738;