5-55226608-C-T

Variant names:

• chr5-55226608-C-T
• rs115971569
• NM_001190787.3:c.277G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_001190787.3(MCIDAS):​c.277G>A​(p.Ala93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,380,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A93P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0890
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124900978 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06923285).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000029 (4/1380060) while in subpopulation AFR AF = 0.0000957 (3/31348). AF 95% confidence interval is 0.0000254. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	NM_001190787.3	MANE Select	c.277G>A	p.Ala93Thr	missense	Exon 3 of 7	NP_001177716.1	D6RGH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	ENST00000513312.3	TSL:1 MANE Select	c.277G>A	p.Ala93Thr	missense	Exon 3 of 7	ENSP00000426359.1	D6RGH6
	MCIDAS	ENST00000513468.5	TSL:5	n.277G>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000422165.1	I6L8E2
	MCIDAS	ENST00000515336.1	TSL:5	n.214G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1380060 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 680994

African (AFR) AF: 0.0000957 AC: 3 AN: 31348

American (AMR) AF: 0.00 AC: 0 AN: 35228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25008

East Asian (EAS) AF: 0.00 AC: 0 AN: 35200

South Asian (SAS) AF: 0.00 AC: 0 AN: 78846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077250

Other (OTH) AF: 0.00 AC: 0 AN: 57712

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.089
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.034
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.040	D
Vest4		0.10
MutPred		0.20		Gain of glycosylation at A93 (P = 0.0351)
MVP		0.072
ClinPred		0.30	T
GERP RS		1.7
Varity_R		0.078
gMVP		0.059
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115971569; hg19: chr5-54522436;