rs138563328

Variant names:

• chr2-174764402-C-T
• rs138563328
• NM_000079.4:c.-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000079.4(CHRNA1):​c.-8G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,612,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: CHRNA1 NM_000079.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00100
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-174764402-C-T is Benign according to our data. Variant chr2-174764402-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 506697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0025 (381/152258) while in subpopulation AFR AF = 0.00871 (362/41542). AF 95% confidence interval is 0.00797. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.-8G>A		5_prime_UTR	Exon 1 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.-8G>A		5_prime_UTR	Exon 1 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.-8G>A		5_prime_UTR	Exon 1 of 9	ENSP00000261008.5	P02708-2
	CHRNA1	ENST00000409323.1	TSL:1	c.-8G>A		5_prime_UTR	Exon 1 of 6	ENSP00000386684.1	G5E9G9
	ENSG00000236449	ENST00000442996.1	TSL:1	n.322-8347C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000668 AC: 164 AN: 245680 AF XY: 0.000489

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1459788 Hom.: 4 Cov.: 31 AF XY: 0.000273 AC XY: 198 AN XY: 725964

African (AFR) AF: 0.0100 AC: 335 AN: 33452

American (AMR) AF: 0.000561 AC: 25 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5760

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111078

Other (OTH) AF: 0.000813 AC: 49 AN: 60296

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74458

African (AFR) AF: 0.00871 AC: 362 AN: 41542

American (AMR) AF: 0.000784 AC: 12 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00282

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CHRNA1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.54
PhyloP100		0.0010
PromoterAI		-0.017	Neutral
Mutation Taster		=282/18	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: rs138563328; hg19: chr2-175629130;