11-62910364-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000738.3(CHRM1):c.737C>G(p.Pro246Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRM1 NM_000738.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.611

Genes affected

CHRM1 (HGNC:1950): (cholinergic receptor muscarinic 1) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 1 is involved in mediation of vagally-induced bronchoconstriction and in the acid secretion of the gastrointestinal tract. The gene encoding this receptor is localized to 11q13. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHRM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.16676167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM1	NM_000738.3	c.737C>G	p.Pro246Arg	missense_variant	2/2	ENST00000306960.4
LOC124902683	XR_007062701.1	n.87-239G>C		intron_variant, non_coding_transcript_variant
CHRM1	XM_011544742.3	c.737C>G	p.Pro246Arg	missense_variant	2/2
LOC124902683	XR_007062700.1	n.87-239G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM1	ENST00000306960.4	c.737C>G	p.Pro246Arg	missense_variant	2/2	1	NM_000738.3	P1
	ENST00000543624.1	n.71-239G>C		intron_variant, non_coding_transcript_variant		3
CHRM1	ENST00000543973.1	c.737C>G	p.Pro246Arg	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245812 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457634 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 32

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

Aug 12, 2021

The c.737C>G (p.P246R) alteration is located in exon 2 (coding exon 1) of the CHRM1 gene. This alteration results from a C to G substitution at nucleotide position 737, causing the proline (P) at amino acid position 246 to be replaced by an arginine (R). 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	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.0021
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.10	N;N
MutationTaster	Benign	0.54	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.066
Sift	Benign	0.17	T;T
Sift4G	Benign	0.37	T;.
Polyphen		0.97	D;.
Vest4		0.068
MutPred		0.50		Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.41
MPC		0.93
ClinPred		0.38	T
GERP RS		3.6
Varity_R		0.045
gMVP		0.77

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: rs761952375; hg19: chr11-62677836;