2-174747625-T-A

Position:

chr2-174747625-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000079.4(CHRNA1):c.*499A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 166,468 control chromosomes in the GnomAD database, including 6 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 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 0 hom. )

Consequence

CHRNA1
NM_000079.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.851

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-174747625-T-A is Benign according to our data. Variant chr2-174747625-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 893452.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00447 (681/152316) while in subpopulation NFE AF= 0.00415 (282/68022). AF 95% confidence interval is 0.00375. There are 6 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
CHRNA1	NM_000079.4 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	9/9	ENST00000348749.9
CHRNA1	NM_001039523.3 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	10/10
CHRNA1	XM_017003256.2 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	9/9
CHRNA1	XM_017003257.2 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	9/9	1	NM_000079.4	P1	P02708-2
	ENST00000442996.1 linkuse as main transcript	n.321+17801T>A	intron_variant, non_coding_transcript_variant		1
CHRNA1	ENST00000672640.1 linkuse as main transcript	c.*499A>T	3_prime_UTR_variant	10/10
CHRNA1	ENST00000261007.9 linkuse as main transcript		downstream_gene_variant		2			P02708-1

Frequencies

GnomAD3 genomes

AF:

0.00447

AC:

681

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0326

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00415

Gnomad OTH

AF:

0.00191

GnomAD4 exome

AF:

0.00247

AC:

AN:

14152

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

AN XY:

7402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000575

Gnomad4 FIN exome

AF:

0.0150

Gnomad4 NFE exome

AF:

0.00350

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00447

AC:

681

AN:

152316

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

418

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0326

Gnomad4 NFE

AF:

0.00415

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00318

Hom.:

Bravo

AF:

0.00236

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lethal multiple pterygium syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital myasthenic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2021

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.9

DANN

Benign

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over