11-3667423-C-A

Position:

• chr11-3667423-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020402.4(CHRNA10):​c.704G>T​(p.Arg235Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNA10 NM_020402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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]

ACMG classification

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=0.23527578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA10	NM_020402.4	c.704G>T	p.Arg235Leu	missense_variant	4/5	ENST00000250699.2	NP_065135.2
CHRNA10	NM_001303034.2	c.86G>T	p.Arg29Leu	missense_variant	4/5		NP_001289963.1
CHRNA10	NM_001303035.2	c.86G>T	p.Arg29Leu	missense_variant	4/5		NP_001289964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA10	ENST00000250699.2	c.704G>T	p.Arg235Leu	missense_variant	4/5	1	NM_020402.4	ENSP00000250699.2
CHRNA10	ENST00000534359.1	c.157G>T	p.Ala53Ser	missense_variant	4/5	1		ENSP00000437107.1
CHRNA10	ENST00000526599.1	n.*475G>T		non_coding_transcript_exon_variant	4/5	1		ENSP00000432757.1
CHRNA10	ENST00000526599.1	n.*475G>T		3_prime_UTR_variant	4/5	1		ENSP00000432757.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444630 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.704G>T (p.R235L) alteration is located in exon 4 (coding exon 4) of the CHRNA10 gene. This alteration results from a G to T substitution at nucleotide position 704, causing the arginine (R) at amino acid position 235 to be replaced by a leucine (L). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.25	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift4G	Benign	0.71	T
Vest4		0.28
MutPred		0.13		Gain of glycosylation at A53 (P = 0.0012);
MVP		0.60
ClinPred		1.0	D
GERP RS		5.2

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

Other links and lift over

dbSNP: rs1420604123; hg19: chr11-3688653;