rs147488907

Variant names:

• chr2-174759341-C-A
• rs147488907
• NM_000079.4:c.224G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-174759341-C-A
• chr2-174759341-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000079.4(CHRNA1):​c.224G>T​(p.Arg75Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 5 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), PanelApp Australia
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myasthenic syndrome, congenital, 1B, fast-channel

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.224G>T	p.Arg75Leu	missense_variant	Exon 3 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.224G>T	p.Arg75Leu	missense_variant	Exon 3 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.245G>T	p.Arg82Leu	missense_variant	Exon 2 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.245G>T	p.Arg82Leu	missense_variant	Exon 2 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.224G>T	p.Arg75Leu	missense_variant	Exon 3 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251460 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;T;T;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.9	L;L;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N;N;N;N;.;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;T;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;.;D
Polyphen		0.99, 0.99	.;D;.;.;.;D
Vest4		0.82
MutPred		0.71		Loss of disorder (P = 0.1357);Loss of disorder (P = 0.1357);Loss of disorder (P = 0.1357);Loss of disorder (P = 0.1357);.;Loss of disorder (P = 0.1357);
MVP		0.86
MPC		0.97
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.65
gMVP		0.76
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs147488907; hg19: chr2-175624069;