2-232526593-C-G

Variant names:

• chr2-232526593-C-G
• rs77084550
• NM_000751.3:c.117C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000751.3(CHRND):​c.117C>G​(p.Asn39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,824 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (54 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.01
• Publications: 10 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009984076).
• BP6: Variant 2-232526593-C-G is Benign according to our data. Variant chr2-232526593-C-G is described in ClinVar as Benign. ClinVar VariationId is 195100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00345 (525/152312) while in subpopulation EAS AF = 0.0261 (135/5170). AF 95% confidence interval is 0.0225. There are 5 homozygotes in GnomAd4. There are 280 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.117C>G	p.Asn39Lys	missense	Exon 2 of 12	NP_000742.1
	CHRND	NM_001256657.2		c.117C>G	p.Asn39Lys	missense	Exon 2 of 11	NP_001243586.1
	CHRND	NM_001311196.2		c.-155C>G		5_prime_UTR	Exon 2 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.117C>G	p.Asn39Lys	missense	Exon 2 of 12	ENSP00000258385.3
	CHRND	ENST00000543200.5	TSL:2	c.117C>G	p.Asn39Lys	missense	Exon 2 of 11	ENSP00000438380.1
	CHRND	ENST00000955151.1		c.117C>G	p.Asn39Lys	missense	Exon 2 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152194 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00589 AC: 1480 AN: 251246 AF XY: 0.00531

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00349 AC: 5103 AN: 1461512 Hom.: 54 Cov.: 33 AF XY: 0.00347 AC XY: 2524 AN XY: 727074

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.0167 AC: 745 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.0371 AC: 1474 AN: 39698

South Asian (SAS) AF: 0.00362 AC: 312 AN: 86258

European-Finnish (FIN) AF: 0.000151 AC: 8 AN: 53056

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00209 AC: 2319 AN: 1112000

Other (OTH) AF: 0.00351 AC: 212 AN: 60394

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152312 Hom.: 5 Cov.: 33 AF XY: 0.00376 AC XY: 280 AN XY: 74480

African (AFR) AF: 0.000818 AC: 34 AN: 41580

American (AMR) AF: 0.0118 AC: 180 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5170

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68012

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00306 Hom.: 1

Bravo AF: 0.00451

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00535 AC: 649

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00225

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Lethal multiple pterygium syndrome (2)
-	-	1	Congenital myasthenic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.40
Sift	Benign	0.034	D
Sift4G	Uncertain	0.021	D
Polyphen		0.0050	B
Vest4		0.35
MutPred		0.60		Gain of methylation at N39 (P = 0.0101)
MVP		0.89
MPC		0.32
ClinPred		0.043	T
GERP RS		3.8
PromoterAI		0.00060	Neutral
Varity_R		0.35
gMVP		0.74
Mutation Taster		=98/2	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: rs77084550; hg19: chr2-233391303;