rs189442556

Variant names:

• chr2-174753558-G-A
• rs189442556
• NM_000079.4:c.723C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000079.4(CHRNA1):​c.723C>T​(p.Pro241Pro) variant causes a synonymous change. The variant allele was found at a frequency of 0.000593 in 1,614,200 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (8 hom.)
• Consequence: CHRNA1 NM_000079.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.60
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-174753558-G-A is Benign according to our data. Variant chr2-174753558-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 493302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000407 (62/152306) while in subpopulation SAS AF = 0.0102 (49/4826). AF 95% confidence interval is 0.00789. There are 1 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,AD gene

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.723C>T	p.Pro241Pro	synonymous	Exon 6 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.798C>T	p.Pro266Pro	synonymous	Exon 7 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.723C>T	p.Pro241Pro	synonymous	Exon 6 of 9	ENSP00000261008.5	P02708-2
	CHRNA1	ENST00000409323.1	TSL:1	c.723C>T	p.Pro241Pro	synonymous	Exon 6 of 6	ENSP00000386684.1	G5E9G9
	ENSG00000236449	ENST00000442996.1	TSL:1	n.322-19191G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152188 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00115 AC: 288 AN: 251358 AF XY: 0.00160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000612 AC: 895 AN: 1461894 Hom.: 8 Cov.: 31 AF XY: 0.000903 AC XY: 657 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00881 AC: 760 AN: 86258

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

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000728 AC: 81 AN: 1112012

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152306 Hom.: 1 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		3.6
Mutation Taster		=72/28	polymorphism

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: rs189442556; hg19: chr2-175618286;