Genetic Variant CHRNA10:p.Glu385Lys (chr11-3666307-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020402.4(CHRNA10):c.1153G>A(p.Glu385Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CHRNA10
NM_020402.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.865

Variant links:

Genes affected

CHRNA10 (HGNC:13800): (cholinergic receptor nicotinic alpha 10 subunit) Predicted to enable acetylcholine-gated cation-selective channel activity. Acts upstream of or within positive regulation of cytosolic calcium ion concentration. Predicted to be located in membrane. Predicted to be active in cholinergic synapse and neuron projection. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

CHRNA10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.119926184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA10	NM_020402.4 link	c.1153G>A	p.Glu385Lys	missense_variant	Exon 5 of 5	ENST00000250699.2	NP_065135.2	Q9GZZ6
CHRNA10	NM_001303034.2 link	c.535G>A	p.Glu179Lys	missense_variant	Exon 5 of 5		NP_001289963.1	Q9GZZ6
CHRNA10	NM_001303035.2 link	c.535G>A	p.Glu179Lys	missense_variant	Exon 5 of 5		NP_001289964.1	Q9GZZ6C4IXS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNA10	ENST00000250699.2 link	c.1153G>A	p.Glu385Lys	missense_variant	Exon 5 of 5	1	NM_020402.4	ENSP00000250699.2	Q9GZZ6
CHRNA10	ENST00000534359 link	c.*234G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000437107.1	E9PNX2
CHRNA10	ENST00000526599.1 link	n.*924G>A		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000432757.1	E9PNT7
CHRNA10	ENST00000526599.1 link	n.*924G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000432757.1	E9PNT7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249642

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1153G>A (p.E385K) alteration is located in exon 5 (coding exon 5) of the CHRNA10 gene. This alteration results from a G to A substitution at nucleotide position 1153, causing the glutamic acid (E) at amino acid position 385 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.75

M_CAP

Benign

0.0077

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.24

REVEL

Benign

0.14

Sift

Benign

0.26

Sift4G

Benign

0.49

Polyphen

0.21

Vest4

0.23

MutPred

0.49

Gain of methylation at E385 (P = 0.0088);

MVP

0.68

MPC

0.15

ClinPred

0.14

GERP RS

3.6

Varity_R

0.17

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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