5-55227016-C-T

Position:

• chr5-55227016-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001190787.3(MCIDAS):​c.120+3G>A variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0045 in 1,520,420 control chromosomes in the GnomAD database, including 36 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 0.0035 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (31 hom.)
• Consequence: MCIDAS NM_001190787.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.07003
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.30

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]

LOC124900978 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 5-55227016-C-T is Benign according to our data. Variant chr5-55227016-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238618.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00349 (532/152328) while in subpopulation SAS AF= 0.00601 (29/4828). AF 95% confidence interval is 0.00448. There are 5 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCIDAS	NM_001190787.3	c.120+3G>A		splice_donor_region_variant, intron_variant		ENST00000513312.3	NP_001177716.1
LOC124900978	XR_007058773.1	n.399C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCIDAS	ENST00000513312.3	c.120+3G>A		splice_donor_region_variant, intron_variant		1	NM_001190787.3	ENSP00000426359	P1
MCIDAS	ENST00000513468.5	c.120+3G>A		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000422165
MCIDAS	ENST00000515336.1	n.58-85G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00501 AC: 563 AN: 112322 Hom.: 5 AF XY: 0.00521 AC XY: 325 AN XY: 62370

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00692

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00461 AC: 6309 AN: 1368092 Hom.: 31 Cov.: 32 AF XY: 0.00483 AC XY: 3259 AN XY: 675090

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00632

Gnomad4 ASJ exome AF: 0.00366

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00752

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00595

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74498

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00417 Hom.: 2

Bravo AF: 0.00357

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MCIDAS: BP4, BS2 -

Ciliary dyskinesia, primary, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Feb 18, 2020

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.070
dbscSNV1_RF	Benign	0.33
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

LitVar

Other links and lift over

dbSNP: rs186341559; hg19: chr5-54522844;