NM_000751.3:c.1400G>A

Variant names:

• chr2-232535158-G-A
• rs148939701
• NM_000751.3:c.1400G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000751.3(CHRND):​c.1400G>A​(p.Arg467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,160 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 2.85
• Publications: 8 publications found

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]

CHRND Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 3A

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03213197).
• BP6: Variant 2-232535158-G-A is Benign according to our data. Variant chr2-232535158-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194006.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0015 (229/152340) while in subpopulation AMR AF = 0.00333 (51/15308). AF 95% confidence interval is 0.0026. There are 2 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.1400G>A	p.Arg467His	missense	Exon 12 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.1355G>A	p.Arg452His	missense	Exon 11 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.1097G>A	p.Arg366His	missense	Exon 12 of 12	NP_001298125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.1400G>A	p.Arg467His	missense	Exon 12 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.1355G>A	p.Arg452His	missense	Exon 11 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.1199G>A	p.Arg400His	missense	Exon 11 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00113 AC: 284 AN: 251266 AF XY: 0.00115

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00203 AC: 2972 AN: 1461820 Hom.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 1423 AN XY: 727230

African (AFR) AF: 0.000866 AC: 29 AN: 33478

American (AMR) AF: 0.00168 AC: 75 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53370

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00243 AC: 2697 AN: 1112008

Other (OTH) AF: 0.00232 AC: 140 AN: 60392

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74500

African (AFR) AF: 0.000649 AC: 27 AN: 41574

American (AMR) AF: 0.00333 AC: 51 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00160 Hom.: 3

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Lethal multiple pterygium syndrome (2)
-	1	1	not specified (2)
-	-	1	CHRND-related disorder (1)
-	1	-	Congenital myasthenic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.47
MVP		1.0
MPC		0.95
ClinPred		0.082	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.77
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs148939701; hg19: chr2-233399868; COSMIC: COSV99286140; COSMIC: COSV99286140;