2-174754402-G-C

Variant names:

• chr2-174754402-G-C
• rs773509048
• NM_000079.4:c.357C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BP4

The NM_000079.4(CHRNA1):​c.357C>G​(p.Asp119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,778 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

Genes affected

CHRNA1 (HGNC:1955): (cholinergic receptor nicotinic alpha 1 subunit) The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

CHRNA1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 1A

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myasthenic syndrome, congenital, 1B, fast-channel

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.72157 (below the threshold of 3.09). Trascript score misZ: 1.6771 (below the threshold of 3.09). GenCC associations: The gene is linked to lethal multiple pterygium syndrome, congenital myasthenic syndrome 1A, myasthenic syndrome, congenital, 1B, fast-channel, postsynaptic congenital myasthenic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38706073).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	NM_000079.4	MANE Select	c.357C>G	p.Asp119Glu	missense	Exon 5 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.432C>G	p.Asp144Glu	missense	Exon 6 of 10	NP_001034612.1	P02708-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	ENST00000348749.9	TSL:1 MANE Select	c.357C>G	p.Asp119Glu	missense	Exon 5 of 9	ENSP00000261008.5	P02708-2
	CHRNA1	ENST00000409323.1	TSL:1	c.357C>G	p.Asp119Glu	missense	Exon 5 of 6	ENSP00000386684.1	G5E9G9
	ENSG00000236449	ENST00000442996.1	TSL:1	n.322-18347G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250950 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727186

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111970

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Lethal multiple pterygium syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.24	T
Sift4G	Benign	0.46	T
Polyphen		0.95	P
Vest4		0.26
MutPred		0.48		Loss of catalytic residue at G143 (P = 0.1225)
MVP		0.66
MPC		0.27
ClinPred		0.43	T
GERP RS		5.9
Varity_R		0.43
gMVP		0.45
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs773509048; hg19: chr2-175619130;