rs181843638

Variant names:

• chr5-55220703-C-T
• rs181843638
• NM_001190787.3:c.821G>A

Variant summary

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

The NM_001190787.3(MCIDAS):​c.821G>A​(p.Gly274Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,536,024 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00054 (9 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25
• Publications: 3 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055426955).
• BP6: Variant 5-55220703-C-T is Benign according to our data. Variant chr5-55220703-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00125 (190/152368) while in subpopulation AMR AF = 0.00797 (122/15312). AF 95% confidence interval is 0.00682. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.821G>A	p.Gly274Glu	missense	Exon 7 of 7	NP_001177716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	ENST00000513312.3	TSL:1 MANE Select	c.821G>A	p.Gly274Glu	missense	Exon 7 of 7	ENSP00000426359.1
	MCIDAS	ENST00000513468.5	TSL:5	n.*285G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422165.1
	MCIDAS	ENST00000513468.5	TSL:5	n.*285G>A		3_prime_UTR	Exon 7 of 7	ENSP00000422165.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152250 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00386 AC: 519 AN: 134590 AF XY: 0.00271

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000286

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000536 AC: 741 AN: 1383656 Hom.: 9 Cov.: 35 AF XY: 0.000451 AC XY: 308 AN XY: 682756

African (AFR) AF: 0.000285 AC: 9 AN: 31594

American (AMR) AF: 0.0163 AC: 583 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.000308 AC: 11 AN: 35730

South Asian (SAS) AF: 0.000328 AC: 26 AN: 79228

European-Finnish (FIN) AF: 0.00103 AC: 35 AN: 33884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000454 AC: 49 AN: 1078768

Other (OTH) AF: 0.000484 AC: 28 AN: 57898

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152368 Hom.: 1 Cov.: 34 AF XY: 0.00136 AC XY: 101 AN XY: 74512

African (AFR) AF: 0.00111 AC: 46 AN: 41592

American (AMR) AF: 0.00797 AC: 122 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000619 Hom.: 3

Bravo AF: 0.00205

ExAC AF: 0.000169 AC: 3

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ciliary dyskinesia, primary, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.22	T
Polyphen		0.66	P
Vest4		0.091
MVP		0.15
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.20
Mutation Taster		=92/8	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: rs181843638; hg19: chr5-54516531;