NM_000751.3:c.198+14C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000751.3(CHRND):c.198+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 1,610,210 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 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

CHRND
NM_000751.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.74

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 2-232526688-C-T is Benign according to our data. Variant chr2-232526688-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256780.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00049 (715/1457962) while in subpopulation NFE AF = 0.000534 (593/1109802). AF 95% confidence interval is 0.000498. There are 1 homozygotes in GnomAdExome4. There are 365 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. 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	Effect	Exon Rank	Protein
CHRND	NM_000751.3	MANE Select	c.198+14C>T	intron	N/A	NP_000742.1
CHRND	NM_001256657.2		c.198+14C>T	intron	N/A	NP_001243586.1
CHRND	NM_001311196.2		c.-74+14C>T	intron	N/A	NP_001298125.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CHRND	ENST00000258385.8	TSL:1 MANE Select	c.198+14C>T	intron	N/A	ENSP00000258385.3
CHRND	ENST00000543200.5	TSL:2	c.198+14C>T	intron	N/A	ENSP00000438380.1
CHRND	ENST00000449596.5	TSL:4	c.198+14C>T	intron	N/A	ENSP00000404950.1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000618

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000489

AC:

122

AN:

249518

AF XY:

0.000546

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.000273

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000640

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000490

AC:

715

AN:

1457962

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

365

AN XY:

725352

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33416

American (AMR)

AF:

0.000358

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

26082

East Asian (EAS)

AF:

0.000126

AC:

AN:

39570

South Asian (SAS)

AF:

0.000139

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.0000956

AC:

AN:

52298

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000534

AC:

593

AN:

1109802

Other (OTH)

AF:

0.000565

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

101

134

168

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:

0.000374

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41558

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000618

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.00111

Hom.:

Bravo

AF:

0.000563

ClinVar

ClinVar submissions as Germline

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)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.84

(source)

DANN

Benign

0.58

PhyloP100

-1.7

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

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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