2-174749951-G-C

Variant names:

• chr2-174749951-G-C
• rs374391312
• NM_000079.4:c.997C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000079.4(CHRNA1):​c.997C>G​(p.Arg333Gly) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-174749951-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.928

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.997C>G	p.Arg333Gly	missense	Exon 7 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.1072C>G	p.Arg358Gly	missense	Exon 8 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.997C>G	p.Arg333Gly	missense	Exon 7 of 9	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+20127G>C		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1072C>G	p.Arg358Gly	missense	Exon 8 of 10	ENSP00000261007.5	P02708-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.95
MVP		0.93
MPC		1.0
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.94
gMVP		0.95
Mutation Taster		=7/93	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: rs374391312; hg19: chr2-175614679;