chr20-63359551-G-A

Variant names:

• chr20-63359551-G-A
• rs113080067
• NM_000744.7:c.225C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001256573.2(CHRNA4):​c.-322C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,612,656 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CHRNA4 NM_001256573.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.15
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 20-63359551-G-A is Benign according to our data. Variant chr20-63359551-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 73 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256573.2. 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
	CHRNA4	NM_000744.7	MANE Select	c.225C>T	p.Asp75Asp	synonymous	Exon 2 of 6	NP_000735.1
	CHRNA4	NM_001256573.2		c.-322C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001243502.1
	CHRNA4	NM_001256573.2		c.-322C>T		5_prime_UTR	Exon 2 of 6	NP_001243502.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.225C>T	p.Asp75Asp	synonymous	Exon 2 of 6	ENSP00000359285.4
	CHRNA4	ENST00000467563.3	TSL:1	n.277C>T		non_coding_transcript_exon	Exon 2 of 6
	CHRNA4	ENST00000627000.1	TSL:1	n.225C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000486914.1

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000164 AC: 41 AN: 249774 AF XY: 0.000147

Gnomad AFR exome AF: 0.000808

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1460316 Hom.: 0 Cov.: 38 AF XY: 0.000157 AC XY: 114 AN XY: 726446

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52060

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000148 AC: 164 AN: 1111862

Other (OTH) AF: 0.000149 AC: 9 AN: 60360

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.000483 AC XY: 36 AN XY: 74500

African (AFR) AF: 0.00125 AC: 52 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.000427

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.3
DANN	Benign	0.90
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs113080067; hg19: chr20-61990903;