rs199825346

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001190787.3(MCIDAS):c.739C>T(p.Arg247Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,530,240 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R247Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0058 ( 34 hom. )

Consequence

MCIDAS
NM_001190787.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0300

Publications

6 publications found

Variant links:

Genes affected

MCIDAS (HGNC:40050): (multiciliate differentiation and DNA synthesis associated cell cycle protein) This gene encodes a member of the geminin family of proteins. The encoded nuclear protein is required for the generation of multiciliated cells in respiratory epithelium. Mutations in this gene cause a rare mucociliary clearance disorder associated with recurring respiratory infections in human patients, known as reduced generation of multiple motile cilia (RGMC). [provided by RefSeq, Sep 2016]

MCIDAS Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 42
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MCIDAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.00433442).

BP6

Variant 5-55220785-G-A is Benign according to our data. Variant chr5-55220785-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238621.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00374 (569/152304) while in subpopulation NFE AF = 0.00653 (444/68028). AF 95% confidence interval is 0.00603. There are 2 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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_001190787.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	NM_001190787.3	MANE Select	c.739C>T	p.Arg247Trp	missense	Exon 7 of 7	NP_001177716.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MCIDAS	ENST00000513312.3	TSL:1 MANE Select	c.739C>T	p.Arg247Trp	missense	Exon 7 of 7	ENSP00000426359.1
MCIDAS	ENST00000513468.5	TSL:5	n.*203C>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422165.1
MCIDAS	ENST00000513468.5	TSL:5	n.*203C>T		3_prime_UTR	Exon 7 of 7	ENSP00000422165.1

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

568

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00651

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00332

AC:

446

AN:

134210

AF XY:

0.00322

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000942

Gnomad NFE exome

AF:

0.00578

Gnomad OTH exome

AF:

0.00484

GnomAD4 exome

AF:

0.00580

AC:

7994

AN:

1377936

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

3842

AN XY:

678628

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

31440

American (AMR)

AF:

0.00365

AC:

130

AN:

35572

Ashkenazi Jewish (ASJ)

AF:

0.0000797

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35536

South Asian (SAS)

AF:

0.000872

AC:

AN:

79118

European-Finnish (FIN)

AF:

0.000769

AC:

AN:

33808

Middle Eastern (MID)

AF:

0.000548

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00699

AC:

7505

AN:

1074346

Other (OTH)

AF:

0.00393

AC:

226

AN:

57540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

445

891

1336

1782

2227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00374

AC:

569

AN:

152304

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41556

American (AMR)

AF:

0.00255

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00653

AC:

444

AN:

68028

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00502

Hom.:

Bravo

AF:

0.00386

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00856

AC:

ExAC

AF:

0.00139

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ciliary dyskinesia, primary, 42 (1)

not specified (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.022

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.030

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.13

Sift

Benign

0.060

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.18

MVP

0.25

ClinPred

0.032

GERP RS

2.0

Varity_R

0.074

gMVP

0.29

Mutation Taster

=99/1

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