rs6739001

Variant names:

• chr2-174748749-T-A
• rs6739001
• NM_000079.4:c.1073A>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000079.4(CHRNA1):​c.1073A>T​(p.Asp358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,218 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (86 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.60
• Publications: 6 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: Benign. The variant received -19 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 myasthenic syndrome, congenital, 1B, fast-channel, congenital myasthenic syndrome 1A, lethal multiple pterygium syndrome, postsynaptic congenital myasthenic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027716756).
• BP6: Variant 2-174748749-T-A is Benign according to our data. Variant chr2-174748749-T-A is described in ClinVar as Benign. ClinVar VariationId is 128733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

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.1073A>T	p.Asp358Val	missense	Exon 8 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.1148A>T	p.Asp383Val	missense	Exon 9 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.1073A>T	p.Asp358Val	missense	Exon 8 of 9	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+18925T>A		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1148A>T	p.Asp383Val	missense	Exon 9 of 10	ENSP00000261007.5	P02708-1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2879 AN: 152212 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00473 AC: 1188 AN: 251410 AF XY: 0.00363

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00178 AC: 2597 AN: 1461888 Hom.: 72 Cov.: 33 AF XY: 0.00154 AC XY: 1122 AN XY: 727242

African (AFR) AF: 0.0645 AC: 2158 AN: 33478

American (AMR) AF: 0.00313 AC: 140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1112008

Other (OTH) AF: 0.00320 AC: 193 AN: 60396

GnomAD4 genome AF: 0.0189 AC: 2883 AN: 152330 Hom.: 86 Cov.: 33 AF XY: 0.0188 AC XY: 1397 AN XY: 74492

African (AFR) AF: 0.0656 AC: 2726 AN: 41562

American (AMR) AF: 0.00771 AC: 118 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00268 Hom.: 7

Bravo AF: 0.0207

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00575 AC: 698

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Lethal multiple pterygium syndrome (2)
-	-	1	Congenital myasthenic syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.035	D
Sift4G	Benign	0.093	T
Polyphen		0.087	B
Vest4		0.24
MVP		0.87
MPC		0.41
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.72
Mutation Taster		=94/6	polymorphism (auto)

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: rs6739001; hg19: chr2-175613477;