rs1238575890

Variant names:

• chr20-63361149-G-A
• rs1238575890
• NM_000744.7:c.17C>T

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.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,480,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.989

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]

ENSG00000203900 (HGNC:):

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=0.1760582).
• BP6: Variant 20-63361149-G-A is Benign according to our data. Variant chr20-63361149-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 477007.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-471+28C>T		intron_variant	Intron 1 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.201C>T		non_coding_transcript_exon_variant	Exon 1 of 6
LOC100130587	NR_110634.1	n.183-669G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1328762 Hom.: 0 Cov.: 30 AF XY: 0.00000306 AC XY: 2 AN XY: 654378

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: 0.0000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151752 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74082

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Benign	0.091	T
Polyphen		0.0	B
Vest4		0.098
MutPred		0.30		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.56
MPC		0.40
ClinPred		0.25	T
GERP RS		1.5
Varity_R		0.046
gMVP		0.49

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: rs1238575890; hg19: chr20-61992501;