chr20-63361195-G-C

Variant names:

• chr20-63361195-G-C
• rs6090387
• ENST00000467563.3:n.110C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000467563.3(CHRNA4):​n.110C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,453,094 control chromosomes in the GnomAD database, including 407,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35383 hom., cov: 26)
  • Exomes 𝑓: 0.75 (372235 hom.)
• Consequence: CHRNA4 ENST00000467563.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.228
• Publications: 10 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-63361195-G-C is Benign according to our data. Variant chr20-63361195-G-C is described in ClinVar as Benign. ClinVar VariationId is 3255233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.-30C>G		5_prime_UTR_variant	Exon 1 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NR_046317.2	n.155C>G		non_coding_transcript_exon_variant	Exon 1 of 6
CHRNA4	NM_001256573.2	c.-489C>G		5_prime_UTR_variant	Exon 1 of 6		NP_001243502.1
LOC100130587	NR_110634.1	n.183-623G>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.-30C>G		5_prime_UTR_variant	Exon 1 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.677 AC: 101428 AN: 149920 Hom.: 35357 Cov.: 26

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.661

GnomAD2 exomes AF: 0.707 AC: 52306 AN: 73954 AF XY: 0.698

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.772

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.705

Gnomad NFE exome AF: 0.770

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.751 AC: 979257 AN: 1303076 Hom.: 372235 Cov.: 48 AF XY: 0.748 AC XY: 478862 AN XY: 640390

African (AFR) AF: 0.511 AC: 13464 AN: 26366

American (AMR) AF: 0.766 AC: 19024 AN: 24840

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 16593 AN: 22970

East Asian (EAS) AF: 0.432 AC: 12244 AN: 28326

South Asian (SAS) AF: 0.599 AC: 42400 AN: 70782

European-Finnish (FIN) AF: 0.713 AC: 23147 AN: 32480

Middle Eastern (MID) AF: 0.677 AC: 2622 AN: 3874

European-Non Finnish (NFE) AF: 0.780 AC: 810830 AN: 1039636

Other (OTH) AF: 0.724 AC: 38933 AN: 53802

GnomAD4 genome AF: 0.677 AC: 101490 AN: 150018 Hom.: 35383 Cov.: 26 AF XY: 0.674 AC XY: 49337 AN XY: 73218

African (AFR) AF: 0.525 AC: 21447 AN: 40884

American (AMR) AF: 0.747 AC: 11350 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2544 AN: 3448

East Asian (EAS) AF: 0.417 AC: 2021 AN: 4852

South Asian (SAS) AF: 0.582 AC: 2778 AN: 4774

European-Finnish (FIN) AF: 0.699 AC: 7252 AN: 10382

Middle Eastern (MID) AF: 0.632 AC: 177 AN: 280

European-Non Finnish (NFE) AF: 0.772 AC: 51875 AN: 67234

Other (OTH) AF: 0.665 AC: 1384 AN: 2080

Alfa AF: 0.649 Hom.: 2154

Bravo AF: 0.672

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 87% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 81. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.76
PhyloP100		-0.23
PromoterAI		0.024	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6090387; hg19: chr20-61992547; COSMIC: COSV104427203; COSMIC: COSV104427203;