rs2229957

Variant names:

• chr2-174749988-G-A
• rs2229957
• NM_000079.4:c.960C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-174749988-G-A
• chr2-174749988-G-C
• chr2-174749988-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000079.4(CHRNA1):​c.960C>T​(p.His320His) variant causes a synonymous change. The variant allele was found at a frequency of 0.0732 in 1,613,996 control chromosomes in the GnomAD database, including 5,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (827 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4971 hom.)
• Consequence: CHRNA1 NM_000079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.79
• Publications: 16 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=-0.37).
• BP6: Variant 2-174749988-G-A is Benign according to our data. Variant chr2-174749988-G-A is described in ClinVar as Benign. ClinVar VariationId is 128735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.199 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.960C>T	p.His320His	synonymous	Exon 7 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.1035C>T	p.His345His	synonymous	Exon 8 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.960C>T	p.His320His	synonymous	Exon 7 of 9	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+20164G>A		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1035C>T	p.His345His	synonymous	Exon 8 of 10	ENSP00000261007.5	P02708-1

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13892 AN: 152038 Hom.: 820 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0880

GnomAD2 exomes AF: 0.0808 AC: 20297 AN: 251154 AF XY: 0.0863

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0693

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0713 AC: 104276 AN: 1461840 Hom.: 4971 Cov.: 34 AF XY: 0.0751 AC XY: 54650 AN XY: 727224

African (AFR) AF: 0.161 AC: 5393 AN: 33478

American (AMR) AF: 0.0469 AC: 2099 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 1744 AN: 26136

East Asian (EAS) AF: 0.0558 AC: 2213 AN: 39694

South Asian (SAS) AF: 0.197 AC: 17025 AN: 86254

European-Finnish (FIN) AF: 0.0246 AC: 1315 AN: 53414

Middle Eastern (MID) AF: 0.122 AC: 705 AN: 5766

European-Non Finnish (NFE) AF: 0.0620 AC: 68893 AN: 1111980

Other (OTH) AF: 0.0810 AC: 4889 AN: 60394

GnomAD4 genome AF: 0.0915 AC: 13925 AN: 152156 Hom.: 827 Cov.: 32 AF XY: 0.0916 AC XY: 6815 AN XY: 74390

African (AFR) AF: 0.153 AC: 6349 AN: 41482

American (AMR) AF: 0.0639 AC: 977 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3468

East Asian (EAS) AF: 0.0611 AC: 316 AN: 5172

South Asian (SAS) AF: 0.210 AC: 1008 AN: 4810

European-Finnish (FIN) AF: 0.0223 AC: 237 AN: 10610

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4505 AN: 68002

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0734 Hom.: 1087

Bravo AF: 0.0933

Asia WGS AF: 0.172 AC: 595 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0701

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		4.8
Mutation Taster		=84/16	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: rs2229957; hg19: chr2-175614716; COSMIC: COSV99650186; COSMIC: COSV99650186;