Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000751.3(CHRND):c.12A>G(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,587,830 control chromosomes in the GnomAD database, including 189,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16495 hom., cov: 31)

Exomes 𝑓: 0.49 ( 172766 hom. )

Consequence

CHRND
NM_000751.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.34

Publications

20 publications found

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]

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

CHRND links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 2-232526227-A-G is Benign according to our data. Variant chr2-232526227-A-G is described in ClinVar as Benign. ClinVar VariationId is 128757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRND	NM_000751.3	MANE Select	c.12A>G	p.Pro4Pro	synonymous	Exon 1 of 12	NP_000742.1
CHRND	NM_001256657.2		c.12A>G	p.Pro4Pro	synonymous	Exon 1 of 11	NP_001243586.1
CHRND	NM_001311196.2		c.-260A>G		5_prime_UTR	Exon 1 of 12	NP_001298125.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRND	ENST00000258385.8	TSL:1 MANE Select	c.12A>G	p.Pro4Pro	synonymous	Exon 1 of 12	ENSP00000258385.3
CHRND	ENST00000543200.5	TSL:2	c.12A>G	p.Pro4Pro	synonymous	Exon 1 of 11	ENSP00000438380.1
CHRND	ENST00000449596.5	TSL:4	c.12A>G	p.Pro4Pro	synonymous	Exon 1 of 5	ENSP00000404950.1

Frequencies

GnomAD3 genomes

AF:

0.465

AC:

69913

AN:

150440

Hom.:

16475

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.486

Gnomad EAS

AF:

0.688

Gnomad SAS

AF:

0.517

Gnomad FIN

AF:

0.518

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.437

GnomAD2 exomes

AF:

0.504

AC:

125831

AN:

249842

AF XY:

0.502

show subpopulations

Gnomad AFR exome

AF:

0.378

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.499

Gnomad EAS exome

AF:

0.693

Gnomad FIN exome

AF:

0.495

Gnomad NFE exome

AF:

0.484

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.492

AC:

707422

AN:

1437272

Hom.:

172766

Cov.:

AF XY:

0.493

AC XY:

352450

AN XY:

714824

show subpopulations

African (AFR)

AF:

0.383

AC:

12438

AN:

32450

American (AMR)

AF:

0.554

AC:

24323

AN:

43910

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

12943

AN:

25242

East Asian (EAS)

AF:

0.656

AC:

25307

AN:

38568

South Asian (SAS)

AF:

0.496

AC:

42634

AN:

85974

European-Finnish (FIN)

AF:

0.518

AC:

26410

AN:

50936

Middle Eastern (MID)

AF:

0.417

AC:

2293

AN:

5500

European-Non Finnish (NFE)

AF:

0.485

AC:

532095

AN:

1095994

Other (OTH)

AF:

0.494

AC:

28979

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18987

37974

56960

75947

94934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15802

31604

47406

63208

79010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.465

AC:

69978

AN:

150558

Hom.:

16495

Cov.:

AF XY:

0.468

AC XY:

34424

AN XY:

73528

show subpopulations

African (AFR)

AF:

0.385

AC:

15804

AN:

41088

American (AMR)

AF:

0.475

AC:

7210

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.486

AC:

1679

AN:

3456

East Asian (EAS)

AF:

0.687

AC:

3470

AN:

5048

South Asian (SAS)

AF:

0.517

AC:

2400

AN:

4642

European-Finnish (FIN)

AF:

0.518

AC:

5385

AN:

10386

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.484

AC:

32628

AN:

67452

Other (OTH)

AF:

0.442

AC:

931

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1971

3942

5913

7884

9855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.472

Hom.:

22656

Bravo

AF:

0.458

Asia WGS

AF:

0.574

AC:

1992

AN:

3478

EpiCase

AF:

0.479

EpiControl

AF:

0.478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Lethal multiple pterygium syndrome (2)

Congenital myasthenic syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.46

(source)

DANN

Benign

0.79

PhyloP100

-4.3

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000751.3:c.12A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over