chr20-63349994-T-C

Position:

• chr20-63349994-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000744.7(CHRNA4):​c.1417A>G​(p.Ser473Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.387

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19566777).
• BP6: Variant 20-63349994-T-C is Benign according to our data. Variant chr20-63349994-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 477002.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1417A>G	p.Ser473Gly	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.889A>G	p.Ser297Gly	missense_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2	n.1626A>G		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1417A>G	p.Ser473Gly	missense_variant	5/6	1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397456 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 688586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.68	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.050	N;.
REVEL	Benign	0.21
Sift	Benign	0.12	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.0020	B;.
Vest4		0.17
MutPred		0.33		Gain of catalytic residue at S473 (P = 0.025);.;
MVP		0.85
MPC		0.37
ClinPred		0.18	T
GERP RS		-0.54
Varity_R		0.053
gMVP		0.24

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: rs1555837484; hg19: chr20-61981346;