rs45622132

Positions:

• chr20-63349861-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000744.7(CHRNA4):​c.1550C>T​(p.Ser517Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,595,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S517S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007138163).
• BP6: Variant 20-63349861-G-A is Benign according to our data. Variant chr20-63349861-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 205001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000302 (46/152328) while in subpopulation EAS AF= 0.00579 (30/5180). AF 95% confidence interval is 0.00417. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1550C>T	p.Ser517Leu	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.1022C>T	p.Ser341Leu	missense_variant	5/6
CHRNA4	NR_046317.2	n.1759C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1550C>T	p.Ser517Leu	missense_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000521 AC: 121 AN: 232030 Hom.: 0 AF XY: 0.000452 AC XY: 57 AN XY: 126110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00478

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.000532

GnomAD4 exome AF: 0.000265 AC: 382 AN: 1442928 Hom.: 1 Cov.: 83 AF XY: 0.000246 AC XY: 176 AN XY: 715124

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.0000922

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00211

Gnomad4 SAS exome AF: 0.0000711

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.000556

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74494

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000481 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.27	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.19
Sift	Benign	0.41	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.0020	B;.
Vest4		0.11
MVP		0.71
MPC		0.52
ClinPred		0.0054	T
GERP RS		2.2
Varity_R		0.087
gMVP		0.18

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: rs45622132; hg19: chr20-61981213;