rs143103435

chr20-63356062-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000744.7(CHRNA4):c.296G>A(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,593,264 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 1.98

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040449172).
• BP6: Variant 20-63356062-C-T is Benign according to our data. Variant chr20-63356062-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205045.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, not_provided=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000179 (260/1454016) while in subpopulation MID AF= 0.000523 (3/5740). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 143 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.296G>A	p.Arg99His	missense_variant	4/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.-251G>A		5_prime_UTR_variant	4/6
CHRNA4	NR_046317.2	n.505G>A		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.296G>A	p.Arg99His	missense_variant	4/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.000201 AC: 28 AN: 139248 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000747

Gnomad ASJ AF: 0.00684

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000613

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000326 AC: 81 AN: 248256 Hom.: 0 AF XY: 0.000400 AC XY: 54 AN XY: 134912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00642

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000179 AC: 260 AN: 1454016 Hom.: 0 Cov.: 33 AF XY: 0.000198 AC XY: 143 AN XY: 723242

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00699

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.000501

GnomAD4 genome AF: 0.000201 AC: 28 AN: 139248 Hom.: 0 Cov.: 28 AF XY: 0.000224 AC XY: 15 AN XY: 66850

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000747

Gnomad4 ASJ AF: 0.00684

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000613

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2019

This alteration is classified as 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. -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.031
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.032	D
Polyphen		0.17	B
Vest4		0.46
MVP		0.78
MPC		0.51
ClinPred		0.11	T
GERP RS		3.2
Varity_R		0.21
gMVP		0.53

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: rs143103435; hg19: chr20-61987414;