2-174749988-G-C

Variant names:

• chr2-174749988-G-C
• rs2229957
• NM_000079.4:c.960C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000079.4(CHRNA1):​c.960C>G​(p.His320Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H320H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79
• Publications: 16 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 5 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, 0.933

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	NM_000079.4	MANE Select	c.960C>G	p.His320Gln	missense	Exon 7 of 9	NP_000070.1
	CHRNA1	NM_001039523.3		c.1035C>G	p.His345Gln	missense	Exon 8 of 10	NP_001034612.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	ENST00000348749.9	TSL:1 MANE Select	c.960C>G	p.His320Gln	missense	Exon 7 of 9	ENSP00000261008.5
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+20164G>C		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1035C>G	p.His345Gln	missense	Exon 8 of 10	ENSP00000261007.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.82		Loss of sheet (P = 0.0817)
MVP		0.96
MPC		0.91
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.88
Mutation Taster		=5/95	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: rs2229957; hg19: chr2-175614716;