dbSNP rs138609765: CHRND:p.Ala15Ala (chr2-232526260-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_000751.3(CHRND):c.45G>A(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,612,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CHRND
NM_000751.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -3.37

Publications

1 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: 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

CHRND links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-232526260-G-A is Benign according to our data. Variant chr2-232526260-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466194.

BP7

Synonymous conserved (PhyloP=-3.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000227 (332/1460676) while in subpopulation MID AF = 0.00186 (10/5368). AF 95% confidence interval is 0.00101. There are 1 homozygotes in GnomAdExome4. There are 174 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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	UniProt
CHRND	NM_000751.3	MANE Select	c.45G>A	p.Ala15Ala	synonymous	Exon 1 of 12	NP_000742.1	Q07001-1
CHRND	NM_001256657.2		c.45G>A	p.Ala15Ala	synonymous	Exon 1 of 11	NP_001243586.1	Q07001-2
CHRND	NM_001311196.2		c.-227G>A		5_prime_UTR	Exon 1 of 12	NP_001298125.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRND	ENST00000258385.8	TSL:1 MANE Select	c.45G>A	p.Ala15Ala	synonymous	Exon 1 of 12	ENSP00000258385.3	Q07001-1
CHRND	ENST00000543200.5	TSL:2	c.45G>A	p.Ala15Ala	synonymous	Exon 1 of 11	ENSP00000438380.1	Q07001-2
CHRND	ENST00000955151.1		c.45G>A	p.Ala15Ala	synonymous	Exon 1 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000329

AC:

AN:

249174

AF XY:

0.000378

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.000872

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000312

Gnomad OTH exome

AF:

0.000823

GnomAD4 exome

AF:

0.000227

AC:

332

AN:

1460676

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33456

American (AMR)

AF:

0.000896

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000267

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00186

AC:

AN:

5368

European-Non Finnish (NFE)

AF:

0.000200

AC:

222

AN:

1111766

Other (OTH)

AF:

0.000415

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000223

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41548

American (AMR)

AF:

0.000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000278

Hom.:

Bravo

AF:

0.000329

EpiCase

AF:

0.000491

EpiControl

AF:

0.000534

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lethal multiple pterygium syndrome (2)

Congenital myasthenic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.86

(source)

DANN

Benign

0.86

PhyloP100

-3.4

PromoterAI

0.0046

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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.

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

Computational scores

Splicing

Publications

Other links and lift over