NM_000079.4:c.235-385C>T

Variant names:

• chr2-174758060-G-A
• rs2646164
• NM_000079.4:c.235-385C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000079.4(CHRNA1):​c.235-385C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,613,942 control chromosomes in the GnomAD database, including 806,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75802 hom., cov: 32)
  • Exomes 𝑓: 1.0 (730412 hom.)
• Consequence: CHRNA1 NM_000079.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00800
• 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), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-174758060-G-A is Benign according to our data. Variant chr2-174758060-G-A is described in ClinVar as Benign. ClinVar VariationId is 257237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.235-385C>T		intron	N/A	NP_000070.1
	CHRNA1	NM_001039523.3		c.235-40C>T		intron	N/A	NP_001034612.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	ENST00000348749.9	TSL:1 MANE Select	c.235-385C>T		intron	N/A	ENSP00000261008.5
	CHRNA1	ENST00000409323.1	TSL:1	c.235-385C>T		intron	N/A	ENSP00000386684.1
	ENSG00000236449	ENST00000442996.1	TSL:1	n.322-14689G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151855 AN: 152226 Hom.: 75743 Cov.: 32

Gnomad AFR AF: 0.992

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 0.999 AC: 248515 AN: 248648 AF XY: 1.00

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1461206 AN: 1461598 Hom.: 730412 Cov.: 41 AF XY: 1.00 AC XY: 726939 AN XY: 727112

African (AFR) AF: 0.990 AC: 33137 AN: 33470

American (AMR) AF: 1.00 AC: 44692 AN: 44710

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86240 AN: 86242

European-Finnish (FIN) AF: 1.00 AC: 53404 AN: 53404

Middle Eastern (MID) AF: 1.00 AC: 5768 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111780 AN: 1111788

Other (OTH) AF: 0.999 AC: 60355 AN: 60386

GnomAD4 genome AF: 0.998 AC: 151973 AN: 152344 Hom.: 75802 Cov.: 32 AF XY: 0.998 AC XY: 74324 AN XY: 74492

African (AFR) AF: 0.992 AC: 41229 AN: 41570

American (AMR) AF: 0.999 AC: 15289 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4825 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68037 AN: 68044

Other (OTH) AF: 1.00 AC: 2116 AN: 2116

Alfa AF: 0.999 Hom.: 13177

Bravo AF: 0.997

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 1A (1)
-	-	1	Lethal multiple pterygium syndrome (1)
-	-	1	Myasthenic syndrome, congenital, 1B, fast-channel (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.87
PhyloP100		0.0080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2646164; hg19: chr2-175622788;