NM_000744.7:c.345C>A

Variant names:

• chr20-63356013-G-T
• rs201033859
• NM_000744.7:c.345C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000744.7(CHRNA4):​c.345C>A​(p.Ser115Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,586 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S115S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.40
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.345C>A	p.Ser115Ser	synonymous	Exon 4 of 6	NP_000735.1
	CHRNA4	NR_046317.2		n.554C>A		non_coding_transcript_exon	Exon 4 of 6
	CHRNA4	NM_001256573.2		c.-202C>A		5_prime_UTR	Exon 4 of 6	NP_001243502.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.345C>A	p.Ser115Ser	synonymous	Exon 4 of 6	ENSP00000359285.4
	CHRNA4	ENST00000467563.3	TSL:1	n.397C>A		non_coding_transcript_exon	Exon 4 of 6
	CHRNA4	ENST00000627000.1	TSL:1	n.*34C>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000486914.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460586 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726602

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111876

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nocturnal frontal lobe epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.76
DANN	Benign	0.84
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		-5.4
Sift4G	Benign	0.065	T
Vest4		0.30
MVP		0.38
ClinPred		0.050	T
GERP RS		-8.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: -2

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

Other links and lift over

dbSNP: rs201033859; hg19: chr20-61987365; COSMIC: COSV100937285; COSMIC: COSV100937285;