2-232528323-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000751.3(CHRND):​c.305G>A​(p.Arg102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CHRND
NM_000751.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.15
Variant links:
Genes affected
CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a topological_domain Extracellular (size 223) in uniprot entity ACHD_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000751.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHRNDNM_000751.3 linkuse as main transcriptc.305G>A p.Arg102His missense_variant 4/12 ENST00000258385.8 NP_000742.1
CHRNDNM_001256657.2 linkuse as main transcriptc.260G>A p.Arg87His missense_variant 3/11 NP_001243586.1
CHRNDNM_001311196.2 linkuse as main transcriptc.34G>A p.Ala12Thr missense_variant 4/12 NP_001298125.1
CHRNDNM_001311195.2 linkuse as main transcriptc.34G>A p.Ala12Thr missense_variant 4/10 NP_001298124.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHRNDENST00000258385.8 linkuse as main transcriptc.305G>A p.Arg102His missense_variant 4/121 NM_000751.3 ENSP00000258385 P1Q07001-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251490
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000229
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000122
AC:
179
AN:
1461894
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
88
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000144
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000118
Hom.:
0
Bravo
AF:
0.000106
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000218
EpiControl
AF:
0.000474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 26, 2021The c.305G>A (p.R102H) alteration is located in exon 4 (coding exon 4) of the CHRND gene. This alteration results from a G to A substitution at nucleotide position 305, causing the arginine (R) at amino acid position 102 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Lethal multiple pterygium syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 102 of the CHRND protein (p.Arg102His). This variant is present in population databases (rs147919651, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CHRND-related conditions. ClinVar contains an entry for this variant (Variation ID: 466192). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRND protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 03, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Uncertain
0.075
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
.;.;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Uncertain
0.051
D
MutationAssessor
Uncertain
2.1
.;.;M
MutationTaster
Benign
1.0
D;D;D;N
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-4.7
D;D;D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.028
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.63, 0.57
MVP
1.0
MPC
0.99
ClinPred
0.65
D
GERP RS
4.4
Varity_R
0.76
gMVP
0.63

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.

Other links and lift over

dbSNP: rs147919651; hg19: chr2-233393033; COSMIC: COSV51330303; COSMIC: COSV51330303; API