rs17838546

Variant names:

• chr2-174748293-G-A
• rs17838546
• NM_000079.4:c.1243-38C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000079.4(CHRNA1):​c.1243-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,612,898 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (225 hom.)
• Consequence: CHRNA1 NM_000079.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-174748293-G-A is Benign according to our data. Variant chr2-174748293-G-A is described in ClinVar as Benign. ClinVar VariationId is 257233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1645/152306) while in subpopulation NFE AF = 0.0154 (1048/68042). AF 95% confidence interval is 0.0146. There are 16 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR 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.1243-38C>T		intron	N/A	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.1318-38C>T		intron	N/A	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.1243-38C>T		intron	N/A	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+18469G>A		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1318-38C>T		intron	N/A	ENSP00000261007.5	P02708-1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152188 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.0109 AC: 2713 AN: 249274 AF XY: 0.0108

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0154 AC: 22528 AN: 1460592 Hom.: 225 Cov.: 31 AF XY: 0.0149 AC XY: 10839 AN XY: 726622

African (AFR) AF: 0.00236 AC: 79 AN: 33470

American (AMR) AF: 0.00510 AC: 228 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 432 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00302 AC: 260 AN: 86168

European-Finnish (FIN) AF: 0.0217 AC: 1151 AN: 52928

Middle Eastern (MID) AF: 0.00515 AC: 27 AN: 5242

European-Non Finnish (NFE) AF: 0.0175 AC: 19420 AN: 1111924

Other (OTH) AF: 0.0154 AC: 930 AN: 60322

GnomAD4 genome AF: 0.0108 AC: 1645 AN: 152306 Hom.: 16 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74462

African (AFR) AF: 0.00363 AC: 151 AN: 41556

American (AMR) AF: 0.00713 AC: 109 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

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

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4820

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10610

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1048 AN: 68042

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0130 Hom.: 1

Bravo AF: 0.00933

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		1.6
Mutation Taster		=100/0	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: rs17838546; hg19: chr2-175613021;