chr2-174747713-C-T

Variant names:

• chr2-174747713-C-T
• rs560280191
• NM_000079.4:c.*411G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000079.4(CHRNA1):​c.*411G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 261,324 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (2 hom.)
• Consequence: CHRNA1 NM_000079.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.134
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-174747713-C-T is Benign according to our data. Variant chr2-174747713-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332431.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000847 (129/152286) while in subpopulation SAS AF = 0.0083 (40/4820). AF 95% confidence interval is 0.00626. There are 2 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.*411G>A		3_prime_UTR	Exon 9 of 9	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.*411G>A		3_prime_UTR	Exon 10 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.*411G>A		3_prime_UTR	Exon 9 of 9	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+17889C>T		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.*411G>A		3_prime_UTR	Exon 10 of 10	ENSP00000261007.5	P02708-1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00229 AC: 250 AN: 109038 Hom.: 2 Cov.: 0 AF XY: 0.00311 AC XY: 180 AN XY: 57894

African (AFR) AF: 0.00 AC: 0 AN: 3396

American (AMR) AF: 0.00103 AC: 5 AN: 4862

Ashkenazi Jewish (ASJ) AF: 0.00522 AC: 14 AN: 2680

East Asian (EAS) AF: 0.00 AC: 0 AN: 5490

South Asian (SAS) AF: 0.0111 AC: 191 AN: 17166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4888

Middle Eastern (MID) AF: 0.00815 AC: 3 AN: 368

European-Non Finnish (NFE) AF: 0.000479 AC: 31 AN: 64654

Other (OTH) AF: 0.00108 AC: 6 AN: 5534

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74462

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68022

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000680

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome (1)
-	-	1	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.54
PhyloP100		-0.13
Mutation Taster		=99/1	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: rs560280191; hg19: chr2-175612441;