20-63356084-C-G

Position:

chr20-63356084-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000744.7(CHRNA4):c.274G>C(p.Glu92Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000345 in 1,517,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

CHRNA4
NM_000744.7 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 5.75

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 20-63356084-C-G is Benign according to our data. Variant chr20-63356084-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205043.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}. Variant chr20-63356084-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00029 (37/127400) while in subpopulation AMR AF= 0.000509 (6/11780). AF 95% confidence interval is 0.000338. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHRNA4	NM_000744.7 linkuse as main transcript	c.274G>C	p.Glu92Gln	missense_variant, splice_region_variant	4/6	ENST00000370263.9
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-273G>C		splice_region_variant, 5_prime_UTR_variant	4/6
CHRNA4	NR_046317.2 linkuse as main transcript	n.483G>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.274G>C	p.Glu92Gln	missense_variant, splice_region_variant	4/6	1	NM_000744.7	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.000298

AC:

AN:

127308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000595

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:

0.000473

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000408

AC:

AN:

235410

Hom.:

AF XY:

0.000389

AC XY:

AN XY:

128528

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.000629

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000964

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000349

AC:

486

AN:

1390576

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

256

AN XY:

690854

show subpopulations

Gnomad4 AFR exome

AF:

0.000126

Gnomad4 AMR exome

AF:

0.000516

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000214

Gnomad4 NFE exome

AF:

0.000418

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000290

AC:

AN:

127400

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

60354

show subpopulations

Gnomad4 AFR

AF:

0.0000602

Gnomad4 AMR

AF:

0.000509

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000473

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000611

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000415

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 03, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 11, 2021	CHRNA4 NM_000744.6 exon 4 c.274G>A (p.Glu92Gln): This variant has not been reported in the literature and is present in 0.06% (75/119670) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-61987436-C-G). This variant is present in ClinVar (Variation ID:205043). Evolutionary conservation of this residue suggests that this may impact the protein, but computational predictive tools for this variant are conflicting. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 27, 2018

CHRNA4 NM_000744.6 exon 4 c.274G>A (p.Glu92Gln): This variant has not been reported in the literature and is present in 0.06% (75/119670) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-61987436-C-G). This variant is present in ClinVar (Variation ID:205043). Evolutionary conservation of this residue suggests that this may impact the protein, but computational predictive tools for this variant are conflicting. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

CHRNA4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

CHRNA4: PP3, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.64

Sift

Benign

0.22

Sift4G

Benign

0.11

Polyphen

0.89

Vest4

0.79

MVP

0.91

MPC

1.0

ClinPred

0.18

GERP RS

4.2

Varity_R

0.27

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.85

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over