Variant 11-3667391-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020402.4(CHRNA10):c.736C>T(p.Pro246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,601,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

CHRNA10
NM_020402.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA10	NM_020402.4 linkuse as main transcript	c.736C>T	p.Pro246Ser	missense_variant	4/5	ENST00000250699.2	NP_065135.2	Q9GZZ6
CHRNA10	NM_001303034.2 linkuse as main transcript	c.118C>T	p.Pro40Ser	missense_variant	4/5		NP_001289963.1	Q9GZZ6
CHRNA10	NM_001303035.2 linkuse as main transcript	c.118C>T	p.Pro40Ser	missense_variant	4/5		NP_001289964.1	Q9GZZ6C4IXS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHRNA10	ENST00000250699.2 linkuse as main transcript	c.736C>T	p.Pro246Ser	missense_variant	4/5	1	NM_020402.4	ENSP00000250699.2	Q9GZZ6
CHRNA10	ENST00000534359.1 linkuse as main transcript	c.189C>T	p.Cys63Cys	synonymous_variant	4/5	1		ENSP00000437107.1	E9PNX2
CHRNA10	ENST00000526599.1 linkuse as main transcript	n.*507C>T		non_coding_transcript_exon_variant	4/5	1		ENSP00000432757.1	E9PNT7
CHRNA10	ENST00000526599.1 linkuse as main transcript	n.*507C>T		3_prime_UTR_variant	4/5	1		ENSP00000432757.1	E9PNT7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

229158

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000589

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000966

AC:

AN:

1449120

Hom.:

Cov.:

AF XY:

0.00000971

AC XY:

AN XY:

721260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000675

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000811

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000333

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.736C>T (p.P246S) alteration is located in exon 4 (coding exon 4) of the CHRNA10 gene. This alteration results from a C to T substitution at nucleotide position 736, causing the proline (P) at amino acid position 246 to be replaced by a serine (S). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.67

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.85

Loss of stability (P = 0.1605);

MVP

0.94

MPC

0.60

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.83

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