20-63346437-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000744.7(CHRNA4):c.*301C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000869 in 575,692 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.638

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-63346437-G-A is Benign according to our data. Variant chr20-63346437-G-A is described in ClinVar as [Benign]. Clinvar id is 1233246.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000716 (109/152276) while in subpopulation NFE AF= 0.00128 (87/68010). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.*301C>T		3_prime_UTR_variant	6/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.*301C>T		3_prime_UTR_variant	6/6
CHRNA4	NR_046317.2	n.2394C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*301C>T		3_prime_UTR_variant	6/6	1	NM_000744.7	P1
CHRNA4	ENST00000463705.5	n.2833C>T		non_coding_transcript_exon_variant	5/5	1
CHRNA4	ENST00000631289.1	n.499C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000705 AC: 92 AN: 130494 Hom.: 0 AF XY: 0.000632 AC XY: 45 AN XY: 71226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000536

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000923 AC: 391 AN: 423416 Hom.: 0 Cov.: 0 AF XY: 0.000906 AC XY: 211 AN XY: 232860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.0000626

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000675

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.000707

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74434

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000897 Hom.: 0

Bravo AF: 0.000661

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.88
Dann	Benign	0.47

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: rs201041492; hg19: chr20-61977789;