rs758348186

chr20-63350771-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000744.7(CHRNA4):c.640G>A(p.Ala214Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,613,448 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A214A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.00

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 -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• BP6: Variant 20-63350771-C-T is Benign according to our data. Variant chr20-63350771-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578560.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000239 (35/1461608) while in subpopulation AMR AF= 0.00047 (21/44716). AF 95% confidence interval is 0.000314. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 89. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.640G>A	p.Ala214Thr	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.112G>A	p.Ala38Thr	missense_variant	5/6
CHRNA4	NR_046317.2	n.849G>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.640G>A	p.Ala214Thr	missense_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151840 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 251028 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461608 Hom.: 0 Cov.: 89 AF XY: 0.0000193 AC XY: 14 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151840 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74154

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Sep 20, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.024	D;.
Sift4G	Benign	0.082	T;T
Polyphen		0.20	B;.
Vest4		0.80
MutPred		0.52		Gain of sheet (P = 0.0827);.;
MVP		0.83
MPC		1.2
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.77

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: rs758348186; hg19: chr20-61982123; COSMIC: COSV105921853; COSMIC: COSV105921853;