chr5-55222341-G-T

Variant names:

• chr5-55222341-G-T
• rs777031813
• NM_001190787.3:c.441C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001190787.3(MCIDAS):​c.441C>A​(p.Cys147*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,381,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MCIDAS NM_001190787.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0430
• 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-55222341-G-T is Pathogenic according to our data. Variant chr5-55222341-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 209007.Status of the report is no_assertion_criteria_provided, 0 stars.

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.441C>A	p.Cys147*	stop_gained	Exon 5 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.441C>A	p.Cys147*	stop_gained	Exon 5 of 7	ENSP00000426359.1	D6RGH6
	MCIDAS	ENST00000513468.5	TSL:5	n.445C>A		non_coding_transcript_exon	Exon 5 of 7	ENSP00000422165.1	I6L8E2
	MCIDAS	ENST00000515336.1	TSL:5	n.378C>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000749 AC: 1 AN: 133432 AF XY: 0.0000138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1381638 Hom.: 0 Cov.: 31 AF XY: 0.00000440 AC XY: 3 AN XY: 681424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31556

American (AMR) AF: 0.00 AC: 0 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 35660

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077368

Other (OTH) AF: 0.00 AC: 0 AN: 57784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000565 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ciliary dyskinesia, primary, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.66	D
PhyloP100		0.043
Vest4		0.17
GERP RS		3.0
Mutation Taster		=14/186	disease causing (ClinVar)

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: rs777031813; hg19: chr5-54518169;