rs137852807

chr2-174754305-C-Gchr2-174754305-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000079.4(CHRNA1):c.454G>C(p.Val152Leu) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V152I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-174754305-C-G is Pathogenic according to our data. Variant chr2-174754305-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 18385.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.454G>C	p.Val152Leu	missense_variant	5/9	ENST00000348749.9
CHRNA1	NM_001039523.3	c.529G>C	p.Val177Leu	missense_variant	6/10
CHRNA1	XM_017003256.2	c.550G>C	p.Val184Leu	missense_variant	5/9
CHRNA1	XM_017003257.2	c.475G>C	p.Val159Leu	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.454G>C	p.Val152Leu	missense_variant	5/9	1	NM_000079.4	P1
	ENST00000442996.1	n.322-18444C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myasthenic syndrome, congenital, 1B, fast-channel Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D;D;D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0070	D;D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;.;T
Polyphen		1.0, 1.0	.;D;.;.;D
Vest4		0.80
MutPred		0.88		.;Loss of sheet (P = 0.0817);.;.;.;
MVP		0.93
MPC		0.90
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -27

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852807; hg19: chr2-175619033;